CN1248177A - Coated particles, method of making and using - Google Patents

Abstract

A coated particle is disclosed, comprising an inner core containing a matrix and an outer coating, wherein the matrix is substantially composed of at least one ultrastructured liquid phase, or at least one ultrastructured liquid crystal phase, or a combination of both, and the outer coating comprises a non-layered crystalline material. Methods for preparing and using this coated particle are also disclosed.

Description

Coated particles and methods of making and using same

Background of the invention

field of invention

The present invention relates to coated particles, and methods of making and using the same. Such particles can be used to release one or more substances to a selected environment, absorb one or more substances from a selected environment, and adsorb one or more substances from a selected environment.

current technology

Two particle technologies—polymer-coated particles and liposomes—are of interest.

Polymer-coated particles are limited in several ways, as indicated by the diffusional response of their polymer coating to the extinction of chemical and physical initiators. This is due to two factors. On the one hand, it is the high molecular weight of the polymers that reduces their diffusion coefficients and dissolution kinetics. In the second aspect, the neighbor group effect enlarges the curve representing the chemical response to the initiator, such as pH, salinity, oxidation, reduction, ionization, etc. among others. (Neighbor group effects indicate that a chemical change in one monomeric unit of a polymer significantly changes the parameters controlling the chemical transition in each of the adjacent monomeric units). Additionally, most polymers collect chemical moieties that increase the molecular weight distribution. Furthermore, there are a limited number of suitable polymers available for a particular application of polymer-coated particles. This is due to several reasons: Regulatory reasons; Coating processes often require harsh chemical and/or physical conditions such as solvents, free radicals, elevated temperatures, drying, and/or shear required to form particles The mechanical and thermal stability of polymer-coated particles in industrial applications is also limited. In addition, the large-scale use of polymer-coated particles has side effects on the environment, such as when used in agriculture.

Liposomes also exhibit various limitations. These include their physical and chemical instability. Release of the liposome contents usually depends on the destabilization of the liposome structure. In particular, the lack of pores precludes pore-controlled release of these substances. The dual requirement of 1) physically stabilizing the liposomes until release is required, and 2) destabilizing the bilayer when release is required, on the other hand, presents difficulties. (The term liposome is often interchanged with the term "vesicle" and is usually a vesicle dedicated to glycerophospholipids or other natural lipids. A vesicle is a self-supporting, sealed bilayer assembly of thousands of lipid molecules (amphiphiles) , which encapsulates the aqueous phase. The lipid bilayer is a two-dimensional fluid consisting of a hydrophilic head group exposed to an aqueous solution and a hydrophobic tail group that gathers together to repel water. The bilayer structure is also highly dynamically ordered, Because lipids move rapidly in-plane within each half of the bilayer.) See O'Brien.DF and Ramaswami, V. (1989) in Mark-Bikales-Overberger-Menges ^n.d. ed., John Wiley & Somns. Inc., p.108.

Brief description of the invention

It is an object of the present invention to provide coated particles which are suitable for dissolving or containing a variety of substances, including substances which are susceptible to physical, chemical or biological deterioration.

It is an object of the present invention to provide coated particles which release one or more substances disposed within a matrix in their inner core without requiring destabilization of said matrix.

It is an object of the present invention to provide coated particles which, in response to one or more physical or chemical triggers, immediately induce release or uptake of one or more substances to or from a selected environment.

It is an object of the present invention to provide coated granules which offer a wide range of coated granule systems which can meet specific physical, chemical and biological requirements for their application, such as mechanical and thermal stabilization of coated granules in industrial applications , or when used in large quantities in agriculture will not adversely affect the environment.

It is an object of the present invention to provide coated particles which, if necessary, can be provided with a porous coating which allows pore-controlled release of a substance dispensed therein, or pore-controlled uptake of a substance dispensed therein.

A further object of the present invention is to provide coated particles which can be prepared in a simple manner, including, preferably, without harsh physical and/or chemical conditions.

The foregoing and other objects are achieved by coated particles comprising an inner core comprising a matrix and an outer coating. The matrix consists essentially of at least one nanostructured liquid phase, or at least one nanostructured liquid crystal phase, or a combination of both, while the outer coating comprises a non-lamellar crystalline material.

In a preferred embodiment, coated particles can be prepared as follows:

1. providing a volume of a matrix comprising at least one chemical species having a moiety capable of reacting with a second moiety to form non-lamellar crystals, and

2. contacting the amount of the substrate with a fluid containing at least one chemical substance having a second moiety under conditions that form a non-lamellar crystalline material so that the first moiety reacts with the second moiety while feeding the amount of the substrate Applying energy breaks it down into particles.

It can also be prepared as follows:

1. providing a quantity of substrate comprising a solution of a substance capable of forming a non-lamellar crystalline substance insoluble in the substrate, and

2. Making the aforementioned substance insoluble in the matrix while applying energy to this amount of substance to subdivide it into particles.

Or use a combination of both methods.

Brief description of the drawings

Fig. 1 is a vertical cross-sectional view depicting a coated particle of the present invention, comprising an inner core and an outer coating comprising a matrix of 2 x 2 x 2 unit cells;

Figure 2 is a cross-sectional view depicting coated particles of the present invention;

Figure 3 is a scanning electron micrograph of coated particles of the present invention;

Figure 4 is a scanning electron micrograph of another coated particle of the present invention;

Fig. 5 is based on volume-weighted (volume-weighted) particle diameter to cumulative particle diameter to the volume-weighted cumulative particle size distribution curve that the coating particle of the present invention measures;

Fig. 6 is a curve of small angle X-ray scattering intensity versus wave vector q of coated particles of the present invention;

Figure 7 is a graph of detector readings versus time in minutes for comparative particles using high pressure liquid chromatography;

Figure 8 is a graph of detector readings versus time in minutes measured on coated particles of the invention using high pressure liquid chromatography.

Detailed description of the preferred solution

As shown in FIGS. 1 and 2 , the coated particle 1 of the present invention comprises an inner core 10 and an outer coating 20 . The inner core 10 comprises a matrix consisting essentially of an ultrastructural substance selected from the group consisting of:

a. at least one ultrastructural liquid phase,

b. at least one ultrastructure liquid crystal phase and

c. A combination of the following substances

i. At least one ultrastructural liquid phase and

ii. At least one ultrastructural liquid crystal phase.

Liquid phase materials and liquid crystal phase materials can contain solvents (lyotropic) or be solvent-free (thermotropic). Outer coating 20 includes a non-layered crystalline material. Here, “outer coating” means that the coating 20 is located outside the inner core 10 , and is not limited to mean that the outer coating 20 is the outermost layer of the coated particle 1 .

The ultrastructural liquid phase and the ultrastructural liquid crystal phase have unique materials that are important not only for the ease of production of the particles of the invention, but also for the solubility, stability, presentation properties and other properties required for the final coated particles of the invention. Ability is also very important.

In the present invention, for the outer coating 20, a non-layered crystal structure is particularly preferred over a layered (layered) substance, which exhibits bonding and/or filling in all three dimensions. Rigidity, it is well known that lamellar crystal structures are physically and chemically unstable, for example, (a) a droplet emulsion coated with a lamellar liquid crystal layer is unstable (even barely), (b) due to the The movement of guest molecules in the composite is chemically unstable, and (c) graphite has a particularly low hardness and shear modulus compared with diamond.

The coated particles 1 of the present invention have an average caliper diameter of 0.1 micron to 30 micron, preferably about 0.2 micron to about 5 micron. If necessary, a stabilizing layer, such as a polyelectrolyte or a surfactant monolayer, can be provided on the outside of the coated particle 1, that is, the coating 20, to prevent the coated particle 1 from agglomerating.

The coated particles 1 of the present invention can be used in various ways. Due to the release of the outer coating 20, the coated particle 1 can absorb one or more substances from the selected environment, adsorb one or more substances from the selected environment, or release one or more substances distributed in the selected environment to the selected environment. A substance in a matrix, such as an active agent. In addition, some external coatings have pores, such as clathrates or zeolites, and release of these substances is not required to affect the uptake or release of the substance of interest into or out of the matrix, in some cases by using appropriately tuned pore characteristics Very high selectivity can be obtained. Where particles are used to adsorb the compound or compounds of interest, neither porosity nor release of the outer coating 20 is required, however, porosity may be provided on the outer coating by diffusion of the adsorbed species into the matrix. Adsorption points to adsorb new substances, thereby greatly increasing the adsorption capacity. In preferred embodiments, other substances, such as active agents, can be distributed within the matrix for release into a selected environment.

The matrix is:

a. Thermodynamically stable

b. ultrastructural, and

c. Liquid phase or liquid crystal phase or a combination thereof.

Ultrastructure: Here, the term "ultrastructure" or "ultrastructural" referring to the structure of a substance means that the size of the structural unit of the substance is in the order of nanometers (10 ^-9 meters) or tens of nanometers (10×10 ^-9 m). In general, any substance containing domains or particles of 1-100 nm, or layers or filaments of this thickness can be called an ultrastructured substance. (See Dagani, R., "Nanostructured Materials Promise to Advance Range of Technologies", November 23, 1992 C&E News 18(1992)). This term does not include "ceramic glasses", which are crystalline materials in which the crystal size is so small that in wide-angle x-ray No peaks are observed in diffraction, and some physicists may also refer to them as ultrastructured substances; ultrastructured liquid and liquid crystal phases, as defined here, are characterized by their nanometer-sized domains, due to the local chemical composition having many but distinct from adjacent domains, and does not include substances in adjacent domains that have substantially the same local chemical composition but differ in crystal lattice orientation. Therefore, the term "domain" here refers to a spatial region whose Characterized by their specific chemical composition, distinctly different from adjacent domains: these domains are usually hydrophilic (hydrophobic), while adjacent domains are hydrophobic (hydrophilic); in the present invention, the characteristic size of these domains on the nanoscale. (The term "microdomain" generally refers to domains whose dimensions are in the micrometer or nanometer range.)

The ultrastructural liquid and liquid crystalline phases that provide the matrix of the inner core 10 of the coated particles 1 of the invention have a unique variety of properties that are critical not only for the production of the particles of the invention, but also for the final quality of the coated particles. Particularly desirable solubility, stability, appearance properties, and various capabilities are also important. As discussed in detail below when discussing particle production methods, in order to provide ready dispersion with one of the methods described here, it is desirable for the material to have very low water solubility, (otherwise it would dissolve during dispersion, limiting its Dispersibility), and it also requires water—the purpose is to dissolve the water-soluble reactants used in the dispersion and to dissolve a variety of active compounds.

In particular, in order to dissolve hydrophilic (especially charged) and amphoteric compounds, and to maintain not only dissolution but also the proper conformation and activity of sensitive compounds of biological origin such as proteins, the internal matrix must contain a certain amount of water or other polar solvent. From the standpoint of establishing versatility in coating selection, many (perhaps most) of the compounds listed as useful coatings for this invention require reactants that are only soluble in polar solvents. Furthermore, the use of organic solvents to solubilize biological compounds such as proteins is in most cases incompatible and in no case appropriate considering regulatory, environmental and health considerations. Of course, the requirement of being insoluble in water and capable of dissolving water-soluble compounds is opposite, and it is difficult to solve it by using a single, cheap and safe substance.

A very efficient system for meeting such solubility requirements is provided by a lipid-water system, in which there are microdomains, these domains have a very high water content, and at the same time, the hydrophobic domains are in very intimate contact with the aqueous domains. The presence of aqueous domains prevents the precipitation tendency encountered in systems where the water structure is disrupted by highly loaded co-solvents or co-solutes, as for example in concentrated aqueous polymer solutions. At the same time, effective solubility of amphiphilic compounds (as well as hydrophilic compounds) is provided near the hydrophobic domains.

Ultrastructural liquid or liquid crystalline phases with these solubility characteristics are synthetic or semi-synthetic materials that provide a pure, well characterized, easy to produce, inexpensive matrix with the following desirable properties:

a) The versatility of chemical systems that form ultrastructural liquid or liquid crystalline phases, from biolipids ideal for biomolecules, to flocculating surfactants, to glycolipids that bind bacteria, to Surfactants with ionic or reactive groups, etc., provide applications under a wide range of conditions and uses;

b) the following remarkable capabilities of ultrastructured liquid phases or ultrastructured liquid crystal phases: i) to dissolve a wide range of active compounds, including many traditionally insoluble compounds such as Paclitaxel and biopharmaceuticals, avoiding the use of toxic and conventional organic solvents; ii) obtain high concentrations of the active substance with discordant stability; and iii) provide a biochemical environment that preserves its structure and function;

c) ideal thermodynamic stability, which ensures the absence of instabilities that often occur with other media, such as precipitation of active agents, demulsification, melting and uncapsulation, etc.; and

d) Presence of pore space with preselectable micron-scale pore sizes makes it easy to further control the release kinetics even after the coating is triggered to release, especially in the release of proteins and biomacromolecules.

The desired properties of the ultrastructural material of the inner core 10 are derived from several related concepts related to some materials that can use "polar", "non-polar", "amphiphile", according to the surfactant, "Surfactant" and "polar-nonpolar interface", and similarly in terms of block copolymer systems, are described below.

Polarity: Polar compounds (such as water) and polar groups (such as charged head groups on ionic surfactants and lipids) are water-loving or hydrophilic. In the present invention, "polarity" and "Hydrophilic" is basically synonymous. As far as solvents go, water isn't the only polar solvent. Other important polar solvents in the present invention are: glycerol, ethylene glycol, formamide, N-methylformamide, dimethylformamide, ethylammonium nitrate and polyethylene glycol. Note that one of these (polyethylene glycol) is actually a polymer, thus illustrating the range of possibilities. Polyethylene glycol (PEG) of sufficiently low molecular weight is liquid, and although PEG has not been extensively studied as a polar solvent in combination with surfactants, it has been found that PEG can indeed be used with, for example, surfactants such as BRIJ type surfactants. Ultrastructural liquid and liquid crystalline phases are formed, which are non-ionic, with PEG head ethers linked to alkyl chain surfactants. More generally, with regard to polar groups on hydrophilic and amphiphilic molecules (including but not limited to polar solvents and surfactants), it is discussed below which polar groups are effective as surfactant headgroups and which is invalid when many polar groups are listed.

Non-polar: Non-polar (hydrophobic or "oleophilic") compounds include not only paraffin/hydrocarbon/alkane chains of surfactants, but also their modifications, such as perfluoroalkanes, and other hydrophobic groups, Such as the fused ring structures in cholic acid found in cholate surfactants, or the phenyl groups forming the non-polar moiety in TRITON-type surfactants, and from polyethylene (representing a long alkyl chain) to hydrophobic polymers The full range of oligomeric or polymeric chains, such as hydrophobic polypeptide chains on novel peptide-based surfactants, has been studied. Certain non-polar groups and compounds are listed below in the discussion of useful components within ultrastructural phases.

Amphiphiles: Amphiphiles can be defined as compounds containing both hydrophilic and hydrophobic groups, see D.H. Everett, Pure and Applied Chemistry, vol.31.no.6, p.611, 1972. It is important to note that not all amphiphiles are surfactants. For example, butanol is an amphiphile because the butyl group is hydrophobic and the hydroxyl group is hydrophilic, but it is not a surfactant because it does not satisfy the definition given below. There are many amphiphiles, with highly polar groups, whose degree of hydration can be measured, but which do not exhibit surfactant behavior, see R.Laughlin, Advances in liquid crystals, vol.3, p.41 , 1978.

Surfactants: Surfactants are amphiphiles that have two additional properties. First, compared with non-surfactants, at very low concentrations, it can significantly improve the interfacial physical properties of the aqueous phase (including not only the air-water interface, but also the oil-water and solid-water interfaces). Second, surfactant molecules are largely capable of reversibly associating with each other (with a variety of other molecules) to form thermally stable solutions of macroscopic one-phase-aggregates or micelles. Micelles are usually composed of many surfactant molecules (10-1000) and have the size of a colloid. See R. Laughlin, Advances in liquid crystals, vol.3, p.41, 1978. Lipids, especially polar lipids, are generally considered here for discussion purposes to be a type of surfactant, although "lipids" are generally considered a subclass of surfactants, which are not the same as what is commonly called Surfactant compounds have slightly different characteristics. Lipids often, though not always, have two characteristics that, first, they are usually of biological origin, and second, they are more prone to oils and fats than to water. Indeed, the solubility of many compounds called lipids in water is exceptionally low, thus requiring hydrophobic solvents for lower interfacial tension, and reversible self-association, clearly demonstrating that lipids are indeed surfactants. Thus, for example, such a compound can drastically reduce the interfacial tension between oil and water at low concentrations, even though exceptionally low solubility in water may make it difficult to observe a drop in surface tension in aqueous systems; The addition of hydrophobic solvents to lipid-water systems may make the determination of their self-association into ultrastructural liquid and ultrastructural liquid-crystalline phases a particularly simple matter; Medium is difficult.

Indeed, in the study of ultrastructural liquid crystal structures, commonalities between "lipids" and "surfactants"—previously thought to be intrinsically distinct—do become apparent, with both research institutions (lipids, from Biologically, and surfactants, from an industrial perspective) are the same, since ultrastructure is observed in all lipids that act as surfactants. In addition, it also becomes apparent that certain synthetic surfactants exhibit "lipid-like" properties, such as bis(hexadecyl)dimethylammonium bromide, which is entirely synthetic rather than biological sources, hydrophobic solvents are required for convenient representation of their surface activity. On the other hand, certain lipids, such as lysolipids, which are clearly of biological origin, exhibit a phase behavior somewhat like that of typical water-soluble surfactants. In fact, for the purpose of discussing and comparing the properties of self-association and interfacial tension reduction, it is evident that the more meaningful distinction is between single-tailed and double-tailed compounds, where single-tailed compounds generally mean water soluble nature, while double-tailed compounds are usually oily.

Thus, in the present invention, the interfacial tension between water and hydrophobes can be reduced at very low concentrations—regardless of whether the hydrophobes are air or oil—and exhibit reversible self-association to form supermolecules in water or oil or both. Microstructured micelles, inverted micelles, or any amphiphile of bicontinuous morphology are surfactants. The class of lipids simply includes a subclass consisting of surfactants of biological origin.

Polar-nonpolar interface: In surfactant molecules, one split point can be found in the molecule (in some cases, two split points, or even more than two, if there are polar groups at each end one, as in lipid A, which has seven acyl chains and, therefore, seven split points in each molecule), separating the polar and nonpolar parts of the molecule. In any ultrastructural liquid phase or ultrastructural liquid crystalline phase, surfactants form monolayer or bilayer films; in these films, the position of the split point in the molecule describes a separation of polar domains from nonpolar domains. Divided surfaces: This is called a "polar-nonpolar interface", or a "polar-nonpolar dividing interface". For example, in the case of spherical micelles, this interface approximates a sphere inside the outer surface of the micelle, with the polar groups of the surfactant molecules outside the surface and the non-polar chains inside. Be careful not to confuse the micro interface with the macro interface, which separates the two bulky phases that can be seen with the naked eye.

Bicontinuous: In a bicontinuous structure, the geometry is described as two distinct, multi-connected, intertwined subspaces, each continuous in three directions; thus, it is possible to span the entire span, even if channels are restricted to one or the other of these two subspaces. In a bicontinuous structure, each subspace is enriched with one type of substance or group, and two subspaces are occupied by two such substances or groups, each of them in three directions throughout the space extend. Sponge, sandstone, apples, and many slags are all permanent instances in the physical realm, albeit disordered bicontinuous structures. In these examples, one subspace is occupied by a more or less deformable solid, and the other subspace, although it can be considered as a cavity, is occupied by a fluid. Certain lyotropic liquid crystalline states are also examples, with one subspace occupied by amphiphile molecules, which are oriented and aggregated into sheet-like arrangements that are geometrically ordered, and the other subspace occupied by solvent molecules. The related liquid crystalline state contains two incompatible solvent molecules, such as hydrocarbon and water, showing another possibility, where one subspace is enriched in the first solvent and the other subspace is enriched in the second solvent, multi-connected layers The surface in between is rich in oriented surfactant molecules. Certain equilibrium microemulsions containing comparable amounts of hydrocarbons and water and amphiphilic surfactants can be disordered bicontinuous structures maintained in a permanent flocculated disorder due to thermal motion, since there is no evidence of geometric order , but there is clear evidence that they are multi-connected. Bicontinuous morphology also occurs in certain phase-separated block copolymers. See Anderson, D.M. Davis, H.t., Nitsche, J.C.C. and Scriven. L.E. (1990) Advances in Chemical Physics. 77:337.

Chemical Criteria: In the case of surfactants, various criteria are discussed and listed in detail by Robert Laughlin in determining whether a given polar group functions as a surfactant head group, where the definition of surfactant is included in Ultrastructural phases form in water at relatively low concentrations, see R. Laughlin, Advance in Liquid Crystals, 3:41, 1978.

Some of the polar groups given in Laughlin's table cannot serve as surfactant headgroups—thus, for example, an alkyl chain attached to one of these polar groups is not expected to form an ultrastructural liquid phase or Liquid crystal phase, is - aldehyde, ketone, carboxylate, carboxylic acid, isocyanate, amide, acyl cyanoguanidine, acyl amidinourea, acyl biuret, N,N-dimethylamide, nitrosoalkane, nitrate Alkanes, nitrates, nitrites, nitrones, nitrosamines, pyridine N-oxides, nitriles, isonitriles, amine boranes, amine haloboranes, sulfones, phosphine sulfides, arsine sulfides, sulfonamides , sulfamoximine, alcohol (monofunctional), ester (monofunctional), secondary amine, tertiary amine, thiol, thioether, primary, secondary, and tertiary phosphine.

Certain polar groups can act as surfactant headgroups, so, for example, an alkyl chain attached to one of these polar groups is expected to form ultrastructural liquid and liquid-crystalline phases, and these polar groups yes:

a. Anionic: carboxylate (soap), sulfate, sulfamate, sulfonate, thiosulfate, sulfinate, phosphate, phosphonate, nitroamine, tri(alkylsulfonate) Acyl) methides, xanthates;

b. Cationic: ammonium, pyridinium, phosphonium, sulfonium, sulfoxonium;

c. Zwitterionic: amino acetate, phosphonium propane sulfonate, pyridinium ethyl sulfate;

d. Semi-polar: amine oxides, phosphoryl groups, phosphine oxides, arsine oxides, sulfoxides, sulfoximines, sulfonediimines, ammonia amides.

Laughlin also demonstrated that, in general, a given polar group cannot act as a surfactant if the enthalpy of forming a 1:1 association complex with phenol (donor of hydrogen bonding) is less than 5 kcal head base.

Surfactants require an apolar group in addition to a polar headgroup, and again, there is a guideline for an effective apolar group. For alkyl chains, which are of course the most common, n is at least 6 if n is the number of carbon atoms for surfactant association to occur, although at least 8 or 10 are common. The octylamine of interest, n = 8, has just enough polarity for the amine headgroup to act as a headgroup, exhibiting a lamellar phase with water at ambient temperature, and an ultrastructural L2 phase. Warnheim, Y., Bergenstahl, B., Henriksson, U., Malnvik, A.-C. and Nilsson. P. (1987) J. of Colloid and Interface Sci. 118:233. Branched chain hydrocarbons can basically meet the same requirements at the lower limit of n, for example, sodium 2-ethylhexyl sulfate exhibits a full range of liquid crystal phases. Winsor, P.A. (1968) Chem. Rev. 68:1. However, when n is higher, the two cases of linear and branched hydrocarbons are clearly different. For linear, saturated alkyl chains tend to crystallize, so that when n is greater than about 18, the Krafft temperature becomes quite high, and the temperature range of ultrastructural liquid and liquid crystal phases reaches very high temperatures, approaching or exceeding 100 °C , which makes these surfactants much less useful than surfactants with n between 8-18 in most applications of the invention. The range of n can be greatly increased when unsaturation or branching is introduced into the chain. This case of unsaturation can be illustrated by lipids derived from fish oils, whose chains have 22 carbon atoms and have rather low melting points due to the presence of up to 6 double bonds, such as docosahexaene Acids and their derivatives, including monoglycerides, soaps, etc. Furthermore, very high molecular weight polybutadiene is elastomeric at ambient temperature, and block copolymers with polybutadiene blocks are known to produce ultrastructured liquid crystals. Similarly, the introduction of branched chains can produce hydrocarbon polymers such as polypropylene oxide (PPO), which is important as a hydrophobic block in many amphiphilic block copolymer surfactants, such as the PLURONIC series of surface active agent. In surfactants, replacing hydrogen with fluorine, especially perfluorinated chains reduces the requirement for the minimum value of n, such as lithium perfluorooctanoate (n = 8), which has a full range of liquid crystal phases, including mesophase, which in surfactants It is very rare in the system. As discussed elsewhere, other hydrophobic groups, such as those of fused ring structures in cholate soaps (cholate), can also serve as effective nonpolar groups, although these are often A case-by-case approach must be made to determine whether a particular hydrophobic group can confer surfactant properties.

For single-component block copolymers, a relatively simple mean-field statistical theory is sufficient to predict when ultrastructural liquid and liquid crystalline species are produced, which are quite common across the range of block copolymers. If x is the Flory-Huggins interaction parameter between polymer blocks A and B, N is the overall polymerization index of the block copolymer (defined as the number of statistical units or monomeric units in the polymer chain, related to the interaction parameter The definition is consistent), then, when the product xN is greater than 10.5, the ultrastructural liquid phase and liquid crystal phase can be predicted. Leibler, L. (1980) Macromolecules 13:1602. For comparable values, but above this critical value of 10.5, ordered ultrastructural (liquid crystal) phases can be produced, even including bicontinuous cubic phases. Hajduk, D.A., Harper, P.E., Gruner S.M., Honeker, C.C., Kim, G., Thomas, E.L. and Fetters, L.J. (1994) Macromolecules 27:4063.

Ultrastructural liquid phase substances suitable as ultrastructural substances of the matrix may be:

a. Ultrastructure L1 phase material,

b. Ultrastructure L2 phase material,

c. Ultrastructural microemulsions or

d. Ultrastructure L3 phase material.

An ultrastructural liquid phase is characterized by its domain structure, consisting of domains of at least one first and second type (in some cases, three or even more types) having the following properties:

a) chemical groups in domains of the first type are incompatible with groups in domains of the second type (usually each pair of domains of different types are mutually incompatible), so that they are not compatible under the given conditions mixed, while remaining as separate domains, (for example, domains of the first type consist essentially of polar groups such as water and lipid head groups, while domains of the second type consist essentially of nonpolar groups such as hydrocarbon chains , or, domains of the first type are rich in polystyrene, domains of the second type are rich in polyisoprene, and domains of the third type are rich in polyvinylpyrrolidone);

b) The atomic sequence in each domain resembles a liquid rather than a solid, i.e. lacks an ordered lattice of atoms; (as evidenced by the absence of sharp Bragg peak reflections in wide-angle x-ray diffraction);

c) the smallest dimension of substantially all domains (thickness of lamellar domains, diameter of columnar or spherical domains) is nanoscale, (about 1 to about 100 nm); and

d) The domain organization does not exhibit long-range order nor is it consistent with any periodic lattice. This is evidenced by the absence of sharp Bragg peak reflections in small angle x-ray scattering examination of the phase. (Additionally, as seen below, the absence of both high viscosity and birefringence is strong evidence of a liquid phase, not a liquid crystalline phase.)

Regarding each of the liquid phases, surfactant-based systems are first discussed, where the two domains in ultrastructural liquids are "polar" and "nonpolar". In general, following this, block copolymer based systems are discussed. In these systems, the terms "polar" and "nonpolar" may or may not be applicable, but there are "A" type, "B" type domains, etc., where as defined above (in Ultrastructural In the definition of a fluid), the "A" and "B" domains are mutually immiscible.

L1 phase: In the L1 phase of the surfactant system, the polar-nonpolar interface bends towards the nonpolar region, and the particles usually obtained are normal micelles—existing in the water continuous medium. (Here, "water" refers to any polar solvent). When micelles change from spherical to cylindrical due to a change in conditions or composition, they may begin to coalesce, possibly becoming bicontinuous. In addition to being water continuous, hydrophobic domains may connect to form a sample-spanning network; this may also be the L1 phase. In addition, there are some examples of L1 phases that do not have any microstructure. That is, there are no micelles, no defined domains, just surfactant molecules mixing together in unstructured, single-phase liquid solutions and, therefore, not ultrastructured species. These "unstructured solutions" can sometimes be changed to ultrastructured phases by simply changing the composition without any phase transition between them. In other words, thermodynamics does not define a phase boundary between an unstructured solution and an ultrastructured phase. This is of course inverse to the case of transitions between phases with long-range order (liquid crystals or crystals) and phases lacking long-range order (liquids), where thermodynamically defined phase boundaries are required.

For L1 phases occurring in block copolymer-based systems, "polar" and "non-polar" can be omitted, but, in any case, there are two (sometimes multiple) types of domains; We are accustomed to say that the bending direction of the A/B interface is toward the A domain, so a typical ultrastructure consists of A-type domains in the continuous phase of the B-type domain, usually spherical particles. As an example, in polystyrene-polyisoprene diblock copolymers, if the volume fraction of polystyrene blocks is very low, say 10%, a common microstructure is polystyrene-rich spheres located in in a continuous polyisoprene matrix. In contrast, if the volume fraction of polyisoprene in the polystyrene-polyisoprene diblock copolymer is 10%, the polyisoprene-rich spheres are located in the continuous matrix of polystyrene .

Identification of the ultrastructural L1 phase. Because the L1 phase is a liquid, several techniques have been developed to distinguish the ultrastructural L1 phase from the unstructured solution liquid phase. In addition to the experimental investigations discussed below, there is a known knowledge that provides a criterion for determining in advance whether a given system can form an ultrastructured phase or a simple unstructured solution.

Since the formation of ultrastructural liquid phases and ultrastructural liquid crystal phases is a requirement in the definition of surfactants, when identifying ultrastructural liquid phases and unstructured solutions, if there is a certainty that a given compound is in fact a surface Active agent standards, which are extremely valuable, provide many tests for surface activity in addition to the direct analysis of liquids discussed below. Robert Laughlin discusses many criteria in Advance in liquid crystals, 3:41, 1978. First, Laughlin lists the chemical criteria for prior determination of whether a given compound is a surfactant, which is discussed in detail above. Based on this criterion, a compound is expected to form an ultrastructural phase in water if it is expected to be indeed a surfactant. Furthermore, with such compounds, in the presence of water and hydrophobes, ultrastructural phase formation can be expected, usually incorporating at least a portion of the hydrophobe.

When non-surfactant amphiphiles are added to this system, especially amphiphilic organic solvents, such as short-chain alcohols, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, dimethyl sulfoxide, etc., Unstructured liquids are then likely to form, since the action of the organic solvent will usually break up the colloidal aggregation and dissolve all the components together.

Laughlin went on to discuss a number of criteria based on physical observations. A known criterion is the critical micelle concentration (CMC), which is observed in surface tension measurements. If the surface tension of an aqueous solution of the compound in question is plotted as a function of concentration, then at very low concentrations, a dramatic drop in surface tension can be seen if the compound added is indeed a surfactant. At a particular concentration known as CMC, there is a sharp inflection point in the graph as the slope of the line drops sharply towards the right of the CMC, so adding surfactant reduces the surface tension very little. The reason for this is that the surfactant added above the CMC was almost completely incorporated into the resulting micelles rather than the air-water interface.

The second criterion Laughlin cites is the liquid crystal criterion: if a compound forms liquid crystals at high concentrations, then the compounds must be surfactants that will form liquid crystal phases at concentrations lower than they exist. In particular, the L1 phase is frequently found at concentrations of surfactants just below the formation of regular hexagonal, or in some cases in the case of positive non-bicontinuous cubic phase liquid crystals.

Another criterion discussed by Laughlin is based on the temperature difference between the upper limit of the equilibrium segment of the Krafft boundary and the melting point of the anhydrate. The Krafft boundary is the phase diagram curve of the two-component system of compound and water. Below the Krafft line is the crystal, and above the Krafft line is the crystal melt. Therefore, along the Krafft line in a very narrow humidity range, the solubility has a dramatic rise. If it is determined to be a surfactant, the temperature difference is very large, for example, sodium palmitate, the melting point of the anhydrous compound is 228°C, and the temperature of the equilibrium section of the Krafft line is 69°C, the difference is 219°C, Laughlin continues It was discussed that dodecylamine, whose temperature difference is 14°C, corresponds to a small range of liquid crystals in the phase diagram, thus, showing moderate associative colloidal properties. In contrast, neither dodecylmethylamine nor dodecanol have the associative properties of the surfactant type, and the temperature difference is zero for both.

As in the case of liquid crystals, as discussed here, for a given substance, there are many test methods that can be used to determine whether the liquid substance is ultrastructural, and these will be discussed when discussing the L1 phase, although by Appropriately modified they are suitable for all ultrastructural fluids. In such assays it is desirable to combine as many of these features as possible.

Like all liquid phases, the L1 phase is optically isotropic when not flowing. Using deuterated surfactants gave no splitting in ^{the 2} H-NMR band shape.

Furthermore, the L1 phase of surfactant systems generally does not give birefringence even under moderate flow conditions in examinations using cross-polarized filters. In block copolymer based systems the situation is complicated with respect to birefringence because of the possibility of colored birefringence, so this is not a reliable approach in this case.

Returning to the surfactant-based L1 phase, the viscosity is usually quite low, much lower than that of any liquid crystal in the same system.

Using pulsed gradient NMR to measure the effective self-diffusion coefficients of various components, it can be seen that the self-diffusion of surfactants and any hydrophobes added is very low, usually on the order of 10 ^-13 m ² /s, or less (unless the phase is bicontinuous, see below). This is because the main diffusion mode of surfactants and hydrophobes is the overall diffusion of micelles, which is very slow. For the same reason, the diffusion rates of surfactants and hydrophobes should be substantially equal.

Of course, small angle x-ray scattering (SAXS) does not give sharp Bragg peaks in the nanometer range (not any range). However, analyzing the entire curve with several methods from the literature can give the size of the length of the ultrastructure. The apparent radius of gyration can be determined by analyzing the decrease in intensity at low wavenumbers (but not too low compared to the reciprocal of the molecular length of the surfactant); draw the curve of the intensity versus the square of the wavenumber on the graph, take its slope, and deduce Rg (so-called Guinier diagram). The radius of gyration is related to the size of the micellar unit by a known standard formula. This would fall in the submicron range. Furthermore, by plotting the intensity multiplied by the square of the wavenumber versus the wavenumber—the so-called Hosemann diagram—a peak can be found, which can also be correlated with the size of the micelles; the advantage of this is that the interaction between micelles is less sensitive than the radius of gyration.

For the surfactant-based bicontinuous L1 phase, the above changes as follows. First, when a bicontinuous phase occurs, the viscosity increases significantly, as does the stiffness of the surfactant film, which is continuous. In addition, the self-diffusion rate of the surfactant as well as the added hydrophobe (probably added deliberately to the two-component system as a marker) also increases drastically, approaching or even exceeding the value in the lamellar phase of the same system. When performing SAXS analysis, the radius of gyration and the dimensions obtained from the Hosemann plot are all in the ultrastructural range, and these must be interpreted as the characteristic length dimensions of the bicontinuous domain structure, rather than the dimensions of discrete particles. (In some models, such as the interconnected cylinder model of the author's paper or the Talmon-Prager model, the bicontinuous domain structure is represented as a collection of units, although somewhat like "granules", but only in the composition of blocks (blocks) to form the modeled bicontinuous domain structure. is true for continuous geometries).

The same SAXS analysis was carried out for the L1 phase based on the block copolymer. In contrast to this, NMR band shape and self-diffusion measurements are usually not carried out, nor are surface tension measurements carried out. However, in the past, vapor mobility measurements were often used instead of NMR self-diffusion. In particular, if a gas is found to be preferentially soluble in one domain type but not in others, the migration of this gas through the sample can be measured to test the continuity of these domains. If this were possible, the migration through the continuous domains (type B) in the micellar phase should be only slightly slower than through the pure B polymer, whereas the gas migration of the gas confined to the type A domains should be very slow.

The shear modulus of the micelle phase based on the block copolymer was determined by the shear modulus of the polymer block conventionally referred to as Polymer B forming continuous domains. Thus, for example, in a PS-PI diblock polymer with 10% PS, where PS micelles are formed in a continuous PI matrix, the shear modulus should approximate that of pure propene isoprene, There is only a small increase due to the presence of PS micelles. It is of interest that in the opposite case, where PS is 90%, PI micelles in a continuous PS matrix, the elastic PI micelles might provide the shock-absorbing component, which improves the Fracture features.

L2 Phase: This phase is identical to L1 phase, except that the role of the polar and nonpolar domains is reversed: the polar-nonpolar interface bends towards the polar domain, the interior of the micelle (if present) is water and/or other polar species, the nonpolar domains (usually the alkyl chains of lipids) form a continuous matrix—although polar domains may also link to form a bicontinuous L2 phase. As mentioned above, this phase may be ultrastructured or unstructured.

Identification of ultrastructural L2 phases. The guidelines for identifying the ultrastructural L2 phase are the same as above for the L1 phase, with the following modifications. We only need to discuss the surfactant-based L2 phase, because in block copolymer-based systems, the two types of micellar phases (B in A, and A in B) are equivalent, in the above We have discussed the identification of the micellar phase in block copolymer systems.

First, the L2 phase is usually more prominent when the HLB is low, e.g., ethoxylated alcohol surfactants with a low number of ethylene oxide groups (typical alkyl chain lengths are usually 5 or less), or ethoxylated alcohol surfactants with double-chain Surfactant. Regarding phase properties, even compared to inverse liquid crystalline phases, they generally occur at higher concentrations; at higher surfactant concentrations, very common orientations for the L2 phase are close to the inverse hexagonal phase. For the non-bicontinuous L2 phase, which is water self-diffusing, this diffusion is very slow, and measurements of the diffusion coefficient (eg, by pulsed gradient NMR) give values of the order of 10 ¹¹ m ² /s or less. Furthermore, the Hosemann diagram gives the size of the reverse micelles, basically the size of the water domains.

Microemulsion: A microemulsion is defined as a thermodynamically stable, low viscosity, optically isotropic, microstructured liquid phase containing oil (nonpolar liquid), water (polar liquid), and surfactants . See Danielsson, I. and Lindman, B. (1981) Colloids and Surfaces, 3:391. Thermodynamically stable liquid mixtures of surfactants, water, and oil are often referred to as microemulsions. Macroscopically homogeneous, but on microscopic length scales (10-1000 Å), they constitute water- and oil-containing microdomains separated by surfactant-rich films. See Skurtveit. R. and Olsson, U. (1991) J. Phys. Chem. 95:5353. The key defining characteristic of a microemulsion is that it contains "oil" (a non-polar solvent or liquid) along with water and surfactants; always defining the microstructure. Generally speaking, due to the strong phase separation tendency of oil and water, in the absence of organic solvents that can dissolve both oil and water (such as ethanol, THF, dioxane, DMF, acetonitrile, dimethyl sulfoxide, and a small amount of other solvents) When , a clear, single-phase liquid containing oil, water, and surfactant must be a microemulsion, and on this basis alone it can be safely inferred that it is ultrastructural. It should be noted that a microemulsion may also be L1 or L2 phase, especially if it contains defined micelles; however, if it is L1 phase, the micelles must be swollen with oil. This microemulsion is an ultrastructured liquid phase. If the characteristic domain size of a liquid with "oil", water and surfactants is larger than the nanoscale, that is to say in the micrometer range, it is no longer a microemulsion but a "miniemulsion" or ordinary emulsion. Emulsions; the latter two are non-equilibrium. The term microemulsion was introduced, despite the fact that the L1 and L2 phases may contain oil, and may even be bicontinuous, since for a three-component oil-water-surfactant/lipid system, from the water-continuous This continuum of progression from phase to bicontinuous phase to oil continuous phase is quite common, with no phase boundaries in between. In this case, it doesn't make sense to try to establish a cut-off point between the "L1" and "L2" regions of the phase diagram, so it can only be said that the entire region is a "microemulsion" - think that in this region At the high water content end, the structure is of the oil-swollen L1 phase, while at the high oil content end of this region, the structure is of the L2 phase. (On the Venn phase diagram, there is an overlap between the microemulsion and the L1 and L2 phases, but not between L1 and L2). As discussed below, the microstructure of microemulsions is generally described in terms of a surfactant monolayer film that separates oil-rich domains from water-rich domains. This surfactant/lipid-rich segmented membrane can surround to form micelles, or link into a network to form bicontinuous microemulsions.

It should be noted that emulsions are not ultrastructural liquids as referred to here. The characteristic length dimension in emulsions, ie essentially the average size of the emulsion droplets, is usually much larger than in ultrastructured liquids, falling in the micrometer rather than nanometer range. Although recent attempts to produce emulsions with submicron droplet sizes have resulted in emulsions with smaller droplets, referred to as "small emulsions", a crucial distinction, the ultrastructural Liquids do not include emulsions and small emulsions. In contrast to the ultrastructural liquid phases described here, including microemulsions, which exist in thermal equilibrium, emulsions are not equilibrium phases but only metastable species. Also, the default perfectly equilibrated ultrastructural liquid is optically transparent, while emulsions are usually opaque—for example, regular milk is an emulsion. Furthermore, if the Friberg model holds for the structure of ordinary emulsions, as is generally accepted in the art, it can be seen that the differences at the molecular level are quite large. According to this model, emulsion droplets are generally considered to be stabilized by interfacial films, which have been shown to be films of ultrastructural liquid crystalline phase materials by microscopic examination; thus, these emulsions have a hierarchical structure in which the ultrastructural phase Acts as a stabilizing layer between the main constituent clumps, which are the emulsified droplets and the continuum. Our use of "ultrastructure" in place of "microstructure" is based on the property of the more precisely defined term "ultrastructure", which excludes other liquid phases, such as emulsions, which fall into entirely different domains. It is clear that considering the simple geometry, indicating that the emulsion droplet size is on the order of 10 microns, it is possible that the stabilizing film of the liquid crystal layer is not suitable as the interior of the microparticles of the present invention, whose particle size is usually on the order of 1 micron superior.

Determination of the ultrastructure of microemulsions. Ultrastructural microemulsions were determined using the method and guidelines discussed above for the determination of ultrastructural L1 phase, but with the following modifications.

For microemulsions that do not clearly fall into the L1 or L2 phase description—which is another case to be dealt with here—we note that many, if not most, are bicontinuous, with Within a single liquid phase of oil, water, and surfactant, bicontinuity provides strong evidence that the phase is ultrastructural, since emulsions and other ordinary liquids are never bicontinuous. This argument is discussed in "On the demonstration of bicontinuous structures in microemulsions" by Lindman, B., Shinoda, K., Olsson, U., Anderson, D.M., Karlstrom, G. and Wennerstrom, H. (1989) Clloids and Surfaces 38:205 proposed in. A long-established method for demonstrating bicontinuity is to use pulse-gradient NMR to measure the effective self-diffusion coefficients of oil and water separately; usually, it is best to also measure the self-diffusion of surfactants. Conductivity can also be used to determine water continuity, although this is prone to problems associated with the "hopping" process. Fluorescence quenching (fluoresence quinching) is also used in the determination of continuity. Sanchez-Rubio, M., Santos-Vidals, L.M., Rushforth, D.S. and Puig, J.E. (1985) J. Phys. Chem. 89:411. Small-angle neutron and x-ray scattering analysis are also used to detect bicontinuities. Auvtay, L., Cotton, R., Ober, R. and Taupin, J. (1984) J. Phys. Chem. 88:4586. Porod analysis of the SAXS curves was used to deduce the presence of interfaces, thus confirming the presence of ultrastructure. Martino, A. and Kalar, E.W. (1990) J. Phys. Chem. 94:1627. The freeze-fracture electron microscopy method, with extremely fast freezing rates, for the study of microemulsions is the result of decades of research into ultrastructural liquid immobilization methods, and there have been important reviews discussing the reliability of the method and results. Talmon, Y., in K.L. Mittal and P. Bothorel (Eds), Vol.6, Plenum press, New York, 1986, p.1581.

In cases where the oil-water-surfactant liquid phase is not clearly L1 and L2 phases, and there is no evidence of apparent bicontinuity, the analysis used to confirm that it is ultrastructural can be included, and a single technique cannot suffice. . In general, the assay methods discussed in this section, such as SANS or SAXS, NMR self-diffusion, cryo-EM, etc., can be used to rationalize the data in ultrastructural models.

L3 phase: In the phase diagram, L2 phase regions sometimes have protruding "tongues": long, thin protrusions that differ from the normal appearance in simple L2 phase regions. This phenomenon also sometimes occurs in some L1 phase regions, as described below. When looking at these, especially with x-ray and neutron scattering, they are fundamentally different from the L2 phase. In the L2 phase, the surfactant film is usually monolayer with oil (non-polar solvent) on one side and water (polar solvent) on the other. In contrast, in the L3 phase referred to here, the surfactant is bilayered with water (polar solvent) on both sides. The L3 phase is generally considered bicontinuous, and in fact, it has another property of the cubic phase: there are two distinct aqueous networks, interwoven but separated by a bilayer membrane. So the L3 phase is indeed very similar to the cubic phase, but lacks the large-scale order of the cubic phase. The L3 phase originates from the L2 phase, and the L2 phase originates from the L1 phase and has different names. "L3 phase" is used for phases related to L2 phase, and "L3*phase" is used for phases related to L1 phase.

Determination of the ultrastructural L3 phase. Determination of the L3 phase, unlike the other liquid phases discussed here, is a complex problem requiring a combination of several analytical techniques. Now discuss the most important one.

Regardless of the default optically isotropic nature of the L3 phase and the fact that it is a liquid, the L3 phase can have the interesting property of exhibiting fluid birefringence. This is generally associated with a rather high viscosity, much higher than that observed in the L1 and L2 phases and comparable or higher than that of the micellar phase. These properties are of course a consequence of the continuous bilayer, which imposes strong constraints on the topology and geometry of the ultrastructure. Thus, shearing may result in mostly cooperative deformation (and resulting alignment) of bilayers, e.g., unlike the micellar L1 phase, individual micellar units simply displace with shear, in any case, unlike the bilayer Monolayer films are generally more deformable with shear displacement than monolayer films. This interpretation is supported by the fact that the viscosity of the L3 phase is generally a linear function of the surfactant volume fraction. Snabre, P. and Porte, G. (1990) Europhys, Lett. 13:641.

Sophisticated light, neutron and x-ray scattering techniques have been developed for the determination of the ultrastructural L3 phase. Safinya, C.R. Roux, D., Smith, G.S., Singa, S.K., Dimon, P., Clark, N.A. and Bellocq, A.M. (1986) Phys. Rev. Lett. 57:2718; Roux, D. and Safinya, C.R. ( 1988) J. Phys. France 49: 307; Nallet, F., Roux, D. and Prost, J. (1989) J. Phys. France 50: 3147. Analysis by Roux, D., Cates, M.E., Olsson, U., ball, R.C., Nallet, F. and Belloxq, A.M., Europhys, Lett. claims to determine the ultrastructure with two aqueous networks consisting of a surfactant bilayer Separated, a certain symmetry is induced due to the equality of the two meshes.

Fortunately, determining the ultrastructural properties of the L3 phase on the basis of phase behavior is much safer than is typically the case for L1 and L2 or even microemulsion phases. First, because the L3 phase is usually obtained by adding a small amount (a few percent) of oil or other compound to a lamellar or bicontinuous cubic phase, or by slightly increasing the temperature of said phase. Because these liquid crystalline phases are readily demonstrable ultrastructural (especially the Bragg peaks in x-rays), it is believed that when a liquid phase is so close in composition to a liquid crystalline phase, it is also ultrastructural. After that, adding a few percent of oil to the ultrastructured liquid crystal phase, it was almost impossible to turn the liquid crystal into a structureless fluid. Indeed, pulse-gradient NMR self-diffusion measurements in the aerosol OT-brine system show that the self-diffusion behavior in the L3 phase extrapolates very clearly to that of the nearby inverse bicontinuous cubic phase. This L3 phase has been the subject of combined SANS, self-diffusion and cryofracture electron microscopy studies. Strey, R. Jahn, W., Skouri, M., Prote, G., Marignan, J. and Olsson, U., "Structure and Dynamics of Supramolecular Aggregates."; S.H.Chem, J.S.Haung and P.Tartaglia, Eds., Kluwer Academic Publishers, The Neherland. Indeed, in the SANS and SAXS scattering analyzes of the L3 phase, a broad interference peak is often observed on the wavevector corresponding to the d-spacing, which is of the same order of magnitude as that in the bicontinuous cubic phase, near the phase diagram , the authors have developed a model for the ultrastructure of the L3 phase that is an extrapolation of the known bicontinuous cubic phase structure. Anderson. D. M., Wennerstroom, H. and Olsson., U. (1989) J. Phys. Chem. 93:4532.

As a component of coated particles, ultrastructured liquid crystal phase substances can be

a. Ultrastructure normal or anti-cubic phase substances,

b. Ultrastructure positive or negative hexagonal phase substances,

c. ultrastructural normal or anti-mesophase substances, or

d. Ultrastructure lamellar phase material.

Ultrastructural liquid crystal phases are characterized by their domain structure, consisting of domains of at least a first type and a second type (and in some cases three or more types of domains) having the following properties:

a) Chemical species in domains of the first type are incompatible with domains of the second type (in general, each pair of domains of different types is mutually incompatible) so that they are incompatible under the given conditions remain as separate domains without mixing; (e.g., domains of the first type consist essentially of polar species such as water and lipid headgroups, domains of the second type essentially consist of nonpolar species such as hydrocarbyl chains composition of matter; or domains of the first type are polystyrene-rich, polyisoprene-rich of the second type, and polyvinylpyrrolidone-rich of the third type);

b) The atomic ordering within each domain is liquid-like rather than solid-like, lacking a lattice sequence of atoms; (evidenced by the absence of sharp Bragg peaks in wide-angle x-ray diffraction);

c) the smallest dimension (e.g., thickness of a layer, diameter of a pillar or sphere), substantially all domains are at the nanometer scale (i.e., about 1 to about 100 nm); and

d) The domain organization is consistent with the lattice, which can be one-dimensional, two-dimensional or three-dimensional, and its lattice parameter (or cell size) is on the nanometer scale (i.e., about 5 to about 200 nm); therefore, the domain organization is consistent with The 230 space groups (space group) listed in the International Tables of Crystallography are consistent, in the well-designed small-angle x-ray scattering (SAXS) measurement with the d-spacing of the minimum ordered reflection of 3-200nm, by the existence of sharp Confirmed by the Bragg reflection.

Lamellar Phase: A lamellar phase is characterized by:

1. The small-angle x-ray shows that the peaks indexing on the wave number is 1:2:3:4:5...,

2. To the naked eye, the phase is transparent, or exhibits slight or moderate turbidity,

3. In polarized optical microscopy, the phase is birefringent, and the known texture (texture) has been fully described by Rosevear and Winsor (eg, Chem. Rev. 1968, p. 1). The three most well-known textures are "Maltese interlaced", "mosaic" and "oil streak". The Maltese interlacing is the superimposition of two roughly mutually perpendicular dark regions (dry-shot edges) above a roughly annular spot of light (birefringence), resulting in a distinct pattern reminiscent of the WWI German military symbol. Variations in this texture and its sources have been fully described in J. Bellare, Ph.D. Thesis, Univ. of Minnesota, 1987. The "tessellation" grain can be imagined as a densely packed textured deformed Maltese interlacing grain, resulting in dark and light markings weaving together randomly. An 'oily streak' pattern is often seen when a (low viscosity) lamellar phase flows between the glass and the slide; in this pattern, when viewed up close with magnification (400x), long, curved lines can be seen The lines, consisting of fine striations, are roughly perpendicular to the curved lines, like sleepers making up the tracks of a railway (unlike the hexagonal texture discussed below). In some cases, especially if the phase has been gently rubbed between the glass and the slide for some time, the lamellar phase will align so that its optical axis is parallel to the line of sight in the microscope, resulting in birefringence.

For lamellar phases in surfactant-water systems:

1. The viscosity is low enough that the substance flows (for example, when the tube containing the phase is tipped upside down)

2. The self-diffusion rate of all components is high and comparable to the value in the bulk, for example, the effective self-diffusion coefficient of water in lamellar phases is comparable to that in pure water. Because liquid crystal-forming surfactants are generally not liquids at ambient temperature, the self-diffusion coefficient of a surfactant is not an accurate reference. In fact, the effective (measured) self-diffusion coefficient of a surfactant in the lamellar phase is often used as A reference datum for interpreting measurements in other phases.

3. If the head group of the surfactant is deuterated, measure ^{the 2} H NMR band shape, and you can see two sharp peaks, which are split twice, which is the hexagonal phase.

4. Regarding phase behavior, in single-tail surfactant/water systems, lamellar phases are usually produced at high surfactant concentrations, generally higher than 70%, and in double-tail surfactant systems, Usually produced at low concentrations, generally below 50%. Typically extends to considerably higher temperatures than any other liquid crystal phase occurring on the phase diagram.

Lamellar Phases in One-Component Block Copolymer Systems:

1. The shear modulus is usually lower than other liquid crystal phases in the same system.

2. With respect to phase behavior, lamellar phases are usually produced at about 50:50 volume fraction of the two blocks.

Positive hexagonal phase: The positive hexagonal phase is characterized by:

1. Peaks shown by small-angle x-rays are marked as 1:√3:2:√7:3…; usually √(h ² +hk+k ² ), where h and k are integers—Miller of two-dimensional symmetry basis index.

2. To the unaided eye, when perfectly equilibrated, the phase is usually transparent and, therefore, usually quite clear compared to the nearby lamellar phase.

3. In polarized optical microscopy, the phase is birefringent, and the known texture is fully described by Rosevear, and Winsor (eg Chem.Rev.1968, P1). One of the most distinctive is the "fan-like" texture. This texture seems to consist of birefringent spots, within a given spot, thin stripes fanning out, reminiscent of Oriental fans. In adjacent spots, the mutual orientation of the fans is random. Another important difference between lamellar and hexagonal phases: On close inspection at high magnification, unlike lamellar phases, the striations in hexagonal phases turned out not to consist of thin stripes perpendicular to the thick ones.

About the regular hexagonal phase in the surfactant-water system:

1. Medium viscosity, more viscous than the lamellar phase, but much lower than the typical cubic phase (which has a viscosity of millions of centipoises).

2. Compared with the lamellar phase, the self-diffusion coefficient of the surfactant is low, and the self-diffusion coefficient of water is comparable to that of the main body of water.

3. The ² H NMR band pattern with the deuterated surfactant shows splitting, half of the splitting observed in the lamellar phase.

4. With regard to phase behavior, in one-tailed surfactant/water systems, the regular hexagonal phase is usually produced at moderate surfactant concentrations, usually at the level of 50% surfactant, and in general, the regular hexagonal phase is adjacent to The micellar (L1) phase region, although some non-bicontinuous cubic phases may arise in between. In the case of two-tailed surfactants, in a surfactant-water binary system, generally substantially none occurs.

For hexagonal phases in one-component block copolymer systems, the terms "normal" and "trans" are generally not applicable, (although in the case where one block is polar and the other non-polar, in principle are eligible to apply). In the same system, the shear modulus in this hexagonal phase is generally higher than that in the lamellar phase and lower than that in the bicontinuous cubic phase. As for the phase behavior, the hexagonal phase usually occurs when the volume fraction of the two blocks is 35:65. Typically, in each case, the two hexagonal phases will straddle the lamellar phase with the minor components within the columns (this description replaces the "forward/inverse" nomenclature for surfactant systems).

Inverse hexagonal phase: In surfactant-water systems, the confirmation of the reverse hexagonal phase differs from the confirmation of the regular hexagonal phase above only in two respects:

1. The viscosity of the anti-hexagonal phase is usually very high, higher than that of the typical regular hexagonal phase and close to the anti-cubic phase, and

2. Regarding phase behavior, in twin-tailed surfactant/water systems, the reverse hexagonal phase usually occurs at high surfactant concentrations, often extending to or near 100% surfactant. In general, regions of inverse hexagonal phase are adjacent to regions of lamellar phase, which occurs at low surfactant concentrations, although a bicontinuous inverse cubic phase usually develops in between. In many binary systems with single-tailed surfactants, such as many monoglycerides (including glycerol monooleate), PEG-based nonionic surfactants with low HLB, the appearance of the reverse hexagonal phase makes unexpected.

As noted above in the discussion of regular hexagonal phases, the distinction between "normal" and "reverse" hexagonal phases is only meaningful in surfactant systems and not in one-component block copolymer hexagonal phases.

Positive bicontinuous cubic phase: Positive bicontinuous cubic phases are characterized by:

1. Small-angle x-rays reveal peak labeling of three-dimensional spacers of cubic appearance. Among these peak markers, frequently encountered spacers are Ia3d (#230), whose peak markers are √6:√8:14:4:…; Pn3m (#224), whose peak markers are √2:√3 :2:√6:√8:…; and Im3m (#229), whose peaks are labeled √2:√4:√6:√8:√10:…

2. To the unaided eye, a perfectly equilibrated phase is usually transparent and therefore usually quite distinct compared to any nearby lamellar phases.

3. In polarized optical microscopy, the phase is non-birefringent and, therefore, has no optical texture.

For positive bicontinuous cubic phases in surfactant-water systems:

1. High viscosity, much higher than lamellar phase, even higher than typical square phase. The viscosity of most cubic phases is on the order of millions of centipoises.

2. No splitting was observed in the NMR band shape, only one peak corresponding to isotropic motion.

3. With regard to phase behavior, in single-tailed surfactant-water systems, the normal bicontinuous cubic phase usually occurs at fairly high surfactant concentrations, typically at the level of 70% for nonionic surfactants. In general, the positive bicontinuous cubic domain lies between the lamellar and normal hexagonal domains, and its high viscosity and non-birefringence make its identification simple. In two-tailed surfactants, in a surfactant-water binary system, this generally does not occur.

For bicontinuous cubic phases in single-component block copolymer systems, the terms "normal" and "trans" are generally not applicable, (although in cases where one block is polar and the other is nonpolar, from In principle, it is eligible to apply). In the same system, the shear modulus in this bicontinuous cubic phase is usually much higher than that in the lamellar phase and significantly higher than that in the hexagonal phase. With regard to phase behavior, bicontinuous cubic phases are usually produced at a volume fraction of the two blocks of 26:74. Generally, in some cases two bicontinuous cubic phases will straddle a lamellar phase with minor components in columns (this description replaces the "forward/inverse" nomenclature for surfactant systems), hexagonal phase Continuous across cube-layer-cube.

Inverted Bicontinuous Cubic Phase: An inverted bicontinuous cubic phase is characterized by:

In surfactant-water systems, the identification of the inverse bicontinuous cubic phase differs from that of the orthodox bicontinuous cubic phase in only one respect. In terms of phase behavior, the anti-bicontinuous phase is between the lamellar and anti-hexagonal phases, and the ortho-bicontinuous cubic phase is between the lamellar and regular hexagonal phases; therefore, reference should be made to the phase discussion. A good rule is: if the cubic phase is at a higher concentration of water than the lamellar phase, it is positive, and if it is at a higher concentration of surfactant than the lamellar phase, it is negative. In two-tailed surfactant-water systems, the anti-cubic phase usually occurs at high surfactant concentrations, although this is often complicated, since the anti-cubic phase may only exist with the addition of hydrophobes ("oil") or In the case of amphiphiles. The reverse bicontinuous cubic phase does occur in binary systems with single-tailed surfactants, such as many monoglycerides (including monoolein) and many PEG-based nonionic surfactants with low HLB values agents.

It should be noted that in the anti-bicontinuous cubic phase, although not positive, space group #212 is also observed. This phase is obtained from the phase of space group #230. As noted in the discussion of positive bicontinuous cubic phases, the distinction between "normal" and "reverse" bicontinuous phases is only meaningful in surfactant systems, not in monocomponent block copolymer cubic phases .

Positive discrete (non-bicontinuous) cubic phase: Positive non-bicontinuous cubic phases are characterized by:

1. Small-angle x-rays show peak labeling of a three-dimensional space group with a cubic phase appearance. The most frequently encountered space group in surfactant systems is Pm3n (#223), whose peak labels are √2:√4:√5:…, in single-component block copolymers, the most frequently observed space group is Im3m, corresponding to body-centered, sphere-filled, whose peaks are labeled √2:√4:√6:√8:….

2. To the unaided eye, when perfectly equilibrated, the phase is usually transparent and, therefore, very distinct from any associated lamellar phase.

3. In polarized optical microscopy, the phase is non-birefringent, so there are no spots of light.

For a positive discrete cubic phase in a surfactant-water system:

1. High viscosity, much higher than lamellar phase, even higher than typical regular hexagonal phase. Most cubic phases have viscosities on the order of millions of centipoise, whether discrete or continuous.

2. Like the bicontinuous cubic phase, there is no splitting in the NMR band shape, only one isotropic peak.

3. Regarding phase behavior, in single-tail surfactant/water systems, positive discrete cubic phases usually occur at fairly low surfactant concentrations, typically around 40% surfactant for ionic surfactants. The positive discrete cubic phase domain is generally between the normal micellar and normal hexagonal phase domains, and its determination is simple due to its high viscosity and non-birefringence. In the case of two-tailed surfactants, in a surfactant-water binary system, it usually does not happen at all.

For discrete cubic phases in one-component block copolymer systems, the terms "direct" and "trans" are generally not applicable, (although in the case where one block is polar and the other non-polar, in principle are eligible to apply). The shear modulus in such a discrete cubic phase is usually almost entirely dependent on the shear modulus of the polymers forming the blocks in the continuous phase. As for phase behavior, discrete cubic phases generally only occur at fairly low volume fractions of one or the other of the two blocks, 20% or less.

Anti-discrete cubic phase: The anti-discrete cubic phase is characterized by:

In surfactant-water systems, the identification of the inverse discrete cubic phase differs from that of the positive discrete cubic phase described above in three respects:

1. Regarding the phase behavior, the anti-discrete cubic phase is between the layered phase and the anti-hexagonal phase, and the positive discrete cubic phase is between the layered phase and the regular hexagonal phase; therefore, it must refer to the above about distinguishing the regular hexagonal phase from the anti-hexagonal phase discussion. A good rule of thumb is: if the cubic phase is at a higher water concentration than the lamellar phase, it is positive, and if it is at a higher surfactant concentration than the lamellar phase, it is negative. In two-tailed surfactant/water systems, the anti-cubic phase usually occurs at high surfactant concentrations, although this is often complicated because the anti-cubic phase may only exist with the addition of hydrophobes ("oil") or In the case of amphiphiles. Inverse discrete cubic phases do occur in binary systems with single-tailed surfactants, such as many monoglycerides (including monoolein), and many PEG-based nonionic surfactants with low HLB values agents.

2. The observed space group is usually Fd3m., #227.

3. The self-diffusion coefficient of water is very low, while that of any hydrophobe present is high, and that of surfactants is usually very high, comparable to that in lamellar phases.

As noted in the discussion of positive discrete cubic phases, the distinction between "normal" and "reverse" discrete cubic phases is only meaningful in surfactant systems, not in single-component block copolymer discrete cubic phases of.

Mesophase: Mesophase is characterized by:

These phases are very rare, and they occur only in a very narrow region of the phase diagram, if at all. Currently, the structures of many of them are unknown or debated. Mesophases can be classified as follows:

The normal int(1) phase occurs at lower surfactant concentrations than the normal bicontinuous cubic phase and is close to the regular hexagonal phase. The viscosity is usually low, or moderately low, not higher than that of the regular hexagonal phase. This phase is birefringent and its texture generally resembles that of the hexagonal phase. The self-diffusion of the components is similar to that of the hexagonal phase. Small angle x-rays show lower space group symmetry compared to the cubic phase, usually monoclinic. This phase can be distinguished from the ortho-hexagonal phase by fairly sophisticated NMR band shape and SAXS analysis. See Henriksson, U., Blackmore, E.S., Tiddy, G.J.T. and Soderman, O. (1992), J. Phys. Chem. 96:3894. The typical band-shaped splitting is intermediate between the hexagonal phase and the zero-splitting isotropic phase, providing good evidence for mesophases.

The positive int(2) phase is found to approach a lamellar phase at higher surfactant concentrations than the positive bicontinuous cubic phase. In nature and possibly also in structure, it is similar to the positive bicontinuous cubic, except that they are birefringent, and there are some differences in NMR band shape and SAXS analysis. The optical texture is somewhat unusual, in some cases resembling lamellar and in some cases hexagonal, and can be quite rough compared to more common phases. As in the int(1) phase, the space group is low-symmetric, typically rhombohedral or tetragonal, requiring two element parameters to characterize, making SAXS analysis difficult. In general, if the square of the d-spacing ratio does not scale to a simple integer regime, the mesophase structure is a conjecture.

The anti-int(2) phase is found at lower concentrations than the anti-bicontinuous cubic phase, close to a lamellar phase. They are birefringent, which is unusual for NMR band patterns and SAXS analysis. As in the int(1) and int(2) phases, the space group is low-symmetric, usually rhombohedral or tetragonal, requiring two element parameters to characterize it, making SAXS analysis difficult. Despite the presence of Bragg peaks on the SAXS spectrum that do not indicate a cubic or hexagonal phase lattice (they have only one lattice parameter), together with the optical birefringence, this is an intermediate phase. The space group that may be the intermediate bicontinuous phase has been discussed in the paper of the inventor of the present application, D.M.Anderson, Supplement to J.Physique.Proceedings of Workshop on Geometry and Interfaces, Aussois, France, Sept.1990, C7-1 to C7 -18.

When the coated particle 10 is formed but the outer coating 20 has not yet been formed, it is particularly desirable that the ultrastructured liquid phase material or ultrastructured liquid crystal phase material or combination thereof is in equilibrium with water (polar solvent), or more precisely , is in equilibrium with a dilute aqueous solution. Once the coated particle 10 has an outer coating 20, the aforementioned ultrastructural material need not be in equilibrium with water. The liquid phases that can be in equilibrium with water are:

L2 phase (a.k.a. reverse micelles),

microemulsions, and

Phase L3 (but not phase L3*). These complement the liquid crystalline phases that can be in equilibrium with water:

anti-cubic phase,

anti-hexagonal,

anti-mesophase, and

layered phase.

From the viewpoint of preparing the coated particles of the present invention, a phase capable of equilibrating with water is preferred. Preferably, when using the methods described herein to disperse a given phase as a matrix, it is desired that the phase is insoluble in water, or any solvent in which the particles are dispersed. Furthermore, when the internal phase has additional properties that are in equilibrium with an excess of aqueous solution during particle formation, the phase deformation is minimal. Similarly, phase transitions are also likely to be minimal when the internal phase equilibrates with excess aqueous solution under the conditions encountered when or after the particle coating is released, which is advantageous in certain applications.

However, at the moment of particle formation, and often also at the time of application, it is preferred for the matrix to be insoluble in water (generally an external solvent), where in some applications it is advantageous to be soluble in water, which can be used with this invention to complete. For example, consider a matrix consisting of 20% C12E5 (pentaethylene glycol lauryl ether) dissolved in water. At 75°C, this composition produces the L3 phase, which is in equilibrium with an excess of water (dilute solution) The, therefore, this composition is dispersible at 75 °C. However, this internal composition may be soluble in water if the application temperature is between 0-25°C. In fact, C12E5 is generally a water-soluble surfactant at room temperature. It is advantageous if the desired end product is non-greasy, non-comedogenic, or even clear after releasing the coating.

Ultrastructured liquid phase substances can be formed from:

a. Polar solvents and surfactants or

b. Polar solvents, surfactants and amphiphiles or hydrophobes or

c. Block copolymer or

d. Block copolymers and solvents.

Ultrastructured liquid crystalline phase substances can be formed from:

a. Polar solvents and surfactants,

b. Polar solvents, surfactants and amphiphiles or hydrophobes,

c. Block copolymer or

d. Block copolymers and solvents.

Criteria that can be used to select effective polar and non-polar groups to prepare effective surfactants are discussed above under the heading Chemical Criteria. Accordingly, suitable surfactants include those compounds containing two chemical moieties, one being an effectively polar group selected from those groups described in the description of polar groups and the other being selected from a non-polar group Effective non-polar groups of those described in the description of .

Suitable surfactant or block copolymer components (or mixtures thereof) may include:

a. Cationic surfactant

b. Anionic surfactant

c. Semi-polar surfactants

c. Zwitterionic surfactant

i. Especially phospholipids

ii. Lipid mixtures containing phospholipids designed to match the physico-chemical characteristics of biological membranes

d. Monoglycerides

e. PEGylated surfactants

f. One of the above-mentioned substances with aromatic rings

g. Block copolymer

i. Both segments are hydrophobic but immiscible with each other;

ii. Both stages are hydrophilic but immiscible with each other;

iii. One segment is hydrophilic and the other segment is hydrophobic, (i.e. amphipathic)

h. Mixtures of two or more of the above substances.

Suitable lipids include phospholipids (such as phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, or sphingomyelin), or glycolipids (such as MGDG, diacylglucopyranosylglycerol, and LipidA). Other suitable lipids are phospholipids (including phosphatidylcholine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, phosphatidylethanolamine, etc.), sphingolipids (including sphingomyelin), glycolipids ( Such as galactolipids such as MGDG and DGDG, diacylglucopyranosylglycerol and LipidA), salts of cholic acid and related acids such as deoxycholic acid, glycocholic acid, taurocholic acid, etc., gentiobiosyl Isoprenoids, isoprenoids, fatty ceramides, plasmalogens, cerebrosides (including sulfatides), gangliosides, cyclopentanol lipids, dimethylaminopropane Lipids and lysolecithins and other lysolipids derived from the above by removal of an acyl chain.

Other suitable classes of surfactants include anionic, cationic, zwitterionic, semi-polar, PEGylated and amine oxides. Preferred surfactants are:

Anionic--sodium oleate, sodium lauryl sulfate, sodium diethylhexyl sulfosuccinate, sodium dimethylhexyl sulfosuccinate, sodium di-2-ethylacetate, 2-ethylsulfate Sodium hexyl ester, sodium undecane-3-sulfate, sodium ethylphenyl undecanoate, carboxylic acid soaps in the form of IC _n where the chain length n is between 8 and 20 and I is a monovalent counterion such as lithium , sodium, potassium, rubidium, etc.;

Cationic - dimethylammonium and trimethylammonium surfactants with chain lengths from 8 to 20 and with chloride, bromine or sulfate counterions, myristyl-gamma-picoline chloride and with chain lengths from 8 to 18 Alkyl related species, benzalkonium benzoate, double-tailed quaternary ammonium surfactants with chain lengths between 8 and 18 carbons and with bromine, chloride or sulfate counterions;

Nonionic - PEGylated surfactants of the formula C _n E _m , wherein the alkane chain length n is 6 to 20 carbons and the average number m of alkylene oxide groups is 2 to 80; ethoxylated cholesterol;

Zwitterionic and semipolar -N,N,N-Trimethylaminodecimide, an amine oxide surfactant with an alkyl chain length of 8 to 18 carbons; dodecyldimethylaminopropane-1 - Sulfate, lauryldimethylaminobutyrate, dodecyltrimethylenebis(ammonium chloride); decylmethylsulfonediimide; dimethyleicosylaminocaproate, and Relatives of these zwitterionic and semipolar surfactants having an alkyl chain length of 8 to 20.

Preferred surfactants approved by the FDA for injectables include benzalkonium chloride, sodium deoxycholate, myristyl-gamma-picoline chloride, Poloxamer 188, polyoxyl 35 castor oil, sorbitan Alcohol Monopalmitate and Sodium 2-Ethylhexanoate.

Suitable block copolymers are those consisting of two or more immiscible segments selected from the following classes of polymers: polydienes, polypropylenes, polyacrylics and polymethacrylics (including Polyacrylic acid, polymethacrylic acid, polyacrylate, polymethacrylate, polydisubstituted ester, polyacrylamide, polymethacrylamide, etc.), polyvinyl ether, polyethylene Alcohols, polyacetals, polyvinyl ketones, polyvinyl halides, polyvinyl nitriles, polyvinyl esters, polystyrenes, polyphenylenes, polyoxides, polycarbonates, Polyesters, polyanhydrides, polyurethanes, polysulfonates, polysiloxanes, polysulfides, polysulfones, polyamides, polyhydrazides, polyureas, polycarbodiimides Classes, polyphosphazenes, polysilanes, polysilazanes, polybenzoxazoles, polyoxadiazoles, polyoxadiazolines, polythiazoles, polybenzothiazoles, polyisophenylene Tetraimides, polyquinoxalines, polybenzimidazoles, polypiperazines, cellulose derivatives, alginic acid and its salts, chitin, chitosan, glycogen, heparin, pectin , polyphosphazene chloride, polytri-n-butyltin fluoride, polyphosphoryl dimethylamide, poly-2,5-selenene (poly-2,5-seleneneylene), poly-4-n-butylpyridinium bromide , poly 2-N-methylpyridinium iodide, polyallyl ammonium chloride, and polytrimethylene oxide sodium sulfonate. Preferred polymer segments are polyethylene oxide, polypropylene oxide, polybutadiene, polyisoprene, polychloroprene, polyacetylene, polyacrylic acid and its salts, polymethacrylic acid and its salts , polymethylene succinic acid and its salts, polymethyl acrylate, polyethyl acrylate, polybutyl acrylate, polymethyl methacrylate, polypropyl methacrylate, poly N-vinylcarbazole, polypropylene Amide, polyisopropylacrylamide, polymethacrylamide, polyacrylonitrile, polyvinyl acetate, polyvinyl octanoate, polystyrene, polyα-methylstyrene, polystyrenesulfonic acid and its salts, Polybromostyrene, polybutylene oxide, polyacrylaldehyde, polydimethylsiloxane, polyvinylpyridine, polyvinylpyrrolidone, polytetrahydrofuran, polydimethylfulvene, polymethylphenylsiloxane alkanes, polycyclopentadienylvinylenes, polyalkylthiophenes, polyalkylparaphenylenes, alternating ethylene-propylene copolymers, polynorbornene, poly-5-((trimethylsilyloxy ) methyl)norbornene, polythiophenylene, heparin, pectin, chitin, chitosan, and alginic acid and its salts. Particularly preferred block copolymers are styrene-butadiene block copolymers, styrene-isoprene block copolymers, styrene-styrenesulfonic acid block copolymers, ethylene oxide-epoxy Propane block copolymer, styrene-dimethylsiloxane block copolymer, ethylene oxide-styrene block copolymer, norbornene-5-((trimethylsiloxy)methyl ) norbornene block copolymer, acetylene-5-((trimethylsiloxy)methyl)norbornene block copolymer, acetylene-norbornene block copolymer, ethylene oxide-norbornene Bornene block copolymers, butylene oxide-ethylene oxide block copolymers, ethylene oxide-siloxane block copolymers, and isoprene-styrene-2-vinylpyridine ternary block copolymers.

3. The third component: hydrophobe or non-surfactant amphiphile

a. Paraffins or alkenes, other long-chain aliphatic compounds

b. Aromatic compounds such as toluene

c. Long chain alcohols

d. Glycerides (diglycerides or triglycerides)

e. Acylated sorbitans, such as sorbitan triesters (such as sorbitan trioleate), or sesquioleates, or sorbitans with a different number of acyl chains between 2 and 6 mixture

f. Other hydrophobic or non-surfactant amphiphiles or mixtures with one or more of the above

g. None.

Suitable third components (hydrophobes or non-surfactant amphiphiles) include: n-alkanes (where n is 6 to 20), including branched, unsaturated and substituted variants (alkenes, Chlorinated alkanes, etc.), cholesterol and related compounds, terpenes, diterpenes, triterpenes, fatty alcohols, fatty acids, aromatics, cyclohexanes, bicyclic compounds such as naphthalene and naphthols, Quinolines and benzoquinolines, etc., tricyclic compounds such as carbazole, phenothiazine, etc., pigments, chlorophyll, sterols, triglycerides, natural oil extracts (such as clove oil, anise oil, cinnamon oil , coriander oil, eucalyptus oil, peppermint oil), waxes, bilirubin, bromine, iodine, hydrophobic and amphipathic proteins and polypeptides (including bacitracin, casein, receptor proteins, lipid-anchored proteins, etc.), topical Anesthetics (such as butacaine, ecgonine, procaine, etc.), and low molecular weight hydrophobic polymers (see polymers listed above). Particularly preferred third components are: anise oil, clove oil, coriander oil, cinnamon oil, eucalyptus oil, peppermint oil, beeswax, benzoin, benzyl alcohol, benzyl benzoate, naphthol, capsaicin, cetearyl alcohol, Cetyl alcohol, cinnamaldehyde, cocoa butter, coconut oil, cottonseed oil (hydrogenated), cyclohexane, cyclomethicone, dibutyl phthalate, dibutyl sebacate, dioctyl phthalate, DIPAC, Ethyl Phthalate, Ethyl Vanillin, Eugenol, Fumaric Acid, Glyceryl Distearate, Menthol, Methyl Acrylate, Methyl Salicylate, Myristyl Alcohol, Oleic Acid, Oleyl Alcohol, Benzyl Chloride, Paraffin, Peanut Oil, Piperonal, Rapeseed Oil, Rosin, Sesame Oil, Sorbitan Fatty Acid Ester, Squalane, Squalene, Stearic Acid, Triacetin, Trimyristin, Vanillin and Vitamin E.

Polar solvents (or in the case of block copolymers, the preferred solvents) can be:

a. water

b. Glycerin

c. Formamide, N-methylformamide, or dimethylformamide

d. Ethylene glycol or other polyols

e. Ethylammonium nitrate

f. Other non-aqueous polar solvents, such as N-methylstedone, N-methylacetamide, pyridinium chloride, etc.;

g. A mixture of two or more of the above solutions.

Ideal polar solvents are water, glycerol, ethylene glycol, formamide, N-methylformamide, dimethylformamide, ethylammonium nitrate, and polyethylene glycol.

As previously stated, the outer coating 20 may be formed from a non-layered crystalline material. The term "non-layered" is used hereinafter to describe the crystal structure. Lamellar crystalline phases are distinct from lamellar liquid crystalline phases and occur in organic compounds (typically polar lipids), inorganic compounds and organometallic compounds. Although these phases may be truly crystalline substances and thus may exhibit a long-range three-dimensional lattice ordering in space of the constituent atoms (or molecules, in the case of organic crystalline substances), interatomic forces and interactions—which may include shared Valence bonds, ionic bonds, hydrogen bonds, steric interactions, hydrophobic interactions, dispersion forces, etc. - are much stronger between constituent atoms or molecules located in the plane of the sheet than between different sheets. For example, in the layered graphite structure, the atoms in the layers are covalently bonded to each other to form a two-dimensional network, while there is no bonding between different layers, only weak dispersion forces and steric interactions. The lack of strong local interlayer interactions leads to many physicochemical properties making it unsuitable as a coating material in the present invention.

First, weak local interactions between layers inherently compromise the physical integrity of layered crystals. This is demonstrated by the comparison between graphite (layered crystalline carbon) and diamond (crystalline carbon with three-dimensional bonding). Indeed, the fact that graphite is an important ingredient in some lubricants because of the ease with which the layers slide over each other, and the fact that diamond is an abrasive, suggests that layered crystal structures are "liquid-like" (or "liquid-crystal-like") in their response to shear. sex. In fact, this same interlayer sliding effect is the same that causes lamellar liquid crystals to have a much lower viscosity compared to other liquid crystal phases, especially compared to the very high viscosity of the bicontinuous cubic phase. Another indication of this liquid likeness is that graphite has a Mohs hardness of 1.0, while diamond has a Mohs hardness of 10. The "lead" pen (which is graphite) used in daily life shows that graphite loses its integrity under shearing.

Adverse effects associated with lamellar crystal structures are seen in everyday life where no macroscopic shearing is involved. According to the generally accepted emulsion structure model modified by Stig Friberg (as reviewed by Larsson, K. and S. Friberg, Eds. 1990, Food Emulsions, 2nd Edition, Marcel Dekker, Inc. NY), lamellar liquid crystals or usually A layered crystalline coating that stabilizes oil droplets in oil-in-water emulsions and water droplets in water-in-oil emulsions. In commonly encountered emulsions such as milk, ice cream, mayonnaise, etc., the well-known unstable The property--referred to in the field as "demulsification"--is primarily due to the fluidity of these layered coatings. Even in stationary emulsions, these layered coatings are constantly undergoing cracking, flowing, and coalescing, as Over time, any emulsion must eventually succumb to the destabilizing effects of these disruptions.

On another level, layered crystalline materials exhibit chemical instability that precludes their use as coatings in embodiments of the present invention. Considering the case of Werner complexes that are isomorphic with tetrakis(4-picoline)nickel dithiocyanate, which form clathrates, the host lattice contains embedded guest molecules, and in most cases upon removal of guest molecules Create permanent holes. One such Werner complex was used as a coating on particles in Example 22, thereby illustrating the use of the invention in producing particles with fixed, size-controlled and highly selective pore coatings. According to J. Lipkowski, Inclusion Compounds I, Academic Press, London (1984), p.59: "The layered structure of Ni(NCS) ₂ (4-MePy) ₄ is stable only in the presence of guest molecules whereas the β-phase It retains its porosity even in the absence of guest molecules." The literature also discusses the three-dimensional non-layered structure of the β-phase in detail, such as: "...the β-phase...has a three-dimensional crystal cavity system interconnected by molecular-sized channels".

The outer coating 20 can protect the inner core 10 and any active agents or components dispensed therein, for example, from oxidation, hydrolysis, premature release, precipitation, shearing, vacuum, enzymatic attack, degradation by other components in manufacture, and and/or the conditions on the outside of the coated particles, eg during their preparation like pH, ionic strength or the presence of biologically active impurities like proteases or nucleases. Examples of each item are:

Oxidation: e.g. for antioxidants such as vitamin C (as it is very sensitive to oxidation) or unsaturated lipids;

Hydrolysis: e.g. for drugs with unstable ester linkages;

Premature release: e.g. during storage;

Precipitation: e.g. for a protonated (hydrochloride) form of a drug that will deprotonate at human pH to become insoluble;

Shearing: e.g. where post-encapsulation handling compromises shear-sensitive compounds such as proteins;

Vacuum: e.g. where processing involves vacuum drying;

Enzyme invasion: Peptide hormones such as somatotropin-releasing inhibitors (often rapidly enzymatically digested in the body) remain active in circulation until they reach the site of release and action;

Degradation by other components: for example where even a slight reactivity between the components dispensed in the inner core and the outer component can create this problem over a shelf life of months or years;

External pH: e.g. a protonated form of the drug may be encapsulated at a low internal pH to ensure solubility, but does not require a low pH external fluid to upset the stomach;

External ionic strength: e.g. in the case of encapsulated proteins to avoid salting out and denaturation;

External impurities such as proteases or nucleases, etc.: Removal of proteases can be prohibitively expensive when externally containing products derived from bioreactors.

For the outer coating 20, the non-layered crystals may be organic compounds, inorganic compounds, minerals, metals such as gold or other crystalline elemental forms such as iodine or organometallic complexes.

The structure of non-layered crystalline coatings can be

a. Non-porous crystals

b. A crystal with a one-dimensional pore network

c. Crystals with a two-dimensional pore network

d. Crystals with a three-dimensional pore network

The coating can have the following surface charge characteristics:

1. Net cationic charge

a. Under all conditions encountered in normal use or

b. Under certain conditions encountered in one or more steps of use

2. Net anionic charge

a. Under all conditions encountered in normal use or

b. Under certain conditions encountered in one or more steps of use or

3. Non-charged:

a. Only at the isoelectric point or

b. Within a pH range that straddles the normal use range or

c. In the pH range achieved/caused during the use phase (e.g. during particle collection by flocculation)

Examples of suitable non-lamellar crystalline coatings (i.e. compounds which occur in non-lamellar crystalline form in the applicable temperature range and in most cases have low toxicity and environmental impact) are:

Ascorbic Acid; Ascorbyl Palmitate; Aspartic Acid; Benzoin Gum; Beta-Naphthol; Bismuth Subcarbonate; Butylated Hydroxytoluene; Butyl Paraben; Calcium Acetate; Calcium Ascorbate; Calcium Carbonate; Calcium Chloride; Calcium citrate; calcium hydroxide; dicalcium phosphate; tertiary calcium phosphate; calcium pyrophosphate; calcium salicylate; calcium silicate; calcium sulfate; carmine; cetearyl alcohol; cetyl alcohol; cinnamaldehyde; citric acid; hydrochloric acid Cysteine; Dibutyl sebacate; Escin; Iron oxide; Ferric citrate; Ferric iron tetroxide; Gentisic acid; Glutamic acid; Glycine; Gold; Histidine; Hydrochlorothiazide; Iodine; Oxidation Iron; Lauryl sulfate; Leucine; Magnesium; Magnesium aluminum silicate; Magnesium carbonate; Magnesium hydroxide; Magnesium oxide; Magnesium silicate; Magnesium sulfate; Magnesium trisilicate; Maleic acid; D,L-malic acid; Methyl Salicylate; Methyl Paraben; Monosodium Glutamate; Propyl Gallate; Propyl Paraben; Silicon Oxide; Silicon; Silicon Dioxide; Sodium Aluminosilicate; Sodium Aminobenzoate; Sodium Benzoate; Sodium bicarbonate; Sodium bisulfate; Sodium bisulfite; Sodium carbonate; Sodium chloride; Sodium citrate; Sodium metabisulfite; Sodium nitrate; Sodium; Sodium sulfate; Sodium thiosulfate; Succinic acid; Talc; Triturated talc; Tartaric acid; DL-tartaric acid; Tartrazine; Tellurium; Titanium dioxide; Triacetin; Triethyl citrate; Hydroxymethylaminomethane and 2-hydroxy-n-cyclopropylmethylmorphinan hydrochloride; zinc oxide.

Calcium phosphate coatings are of interest in biomedical and pharmaceutical applications because calcium phosphate is a major component of bone, teeth and other tissues. For example, in the treatment of osteoporosis, physiological conditions may trigger the release of appropriate pharmaceutical compounds leading to dissolution of bone (and thus particle coating).

Potassium nitrate is of interest in agricultural applications because the coating also acts as a fertilizer for plants.

Iodine, ascorbic acid, benzoic acid, butylated hydroxytoluene, calcium disodium edetate, gentisic acid, histidine, propyl gallate, and zinc oxide may be particularly useful as crystalline coatings in potential pharmaceutical applications, Because they have relatively low water solubility (generally less than 5%), they are on the FDA list of inert ingredients approved for use in injectable formulations.

Of particular interest as coatings are clathrates. Examples of such materials are as follows:

1. Clathrates and clathrates (some leave permanent porosity when removing guest molecules):

Werner complexes of the form _MX2A4 , where M is a divalent cation (Fe, Co, Ni, Cu, Zn, Cd, Mn, Hg, Cr ₎ , and X is an anionic ligand (NCS ^- , NCO ^- , CN ^- , NO ₃ ^- , Cl ^- , Br ^- , I ^- ), and A is pyridine, α-aralkylamine or isoquinoline substituted with an electrically neutral ligand; examples of A include 4-picoline, 3 , 5-lutidine, 4-phenylpyridine and 4-vinylpyridine. A wide range of guest molecules can be included in these complexes, examples being benzene, toluene, xylene, dichlorobenzene, nitrobenzene, methanol, methyl chloride, argon, krypton, xenon, oxygen, nitrogen, carbon dioxide, carbon disulfide, and the like.

Reversible oxygen-carrying chelates such as bis-salicylaldehyde-ethylenediimide cobalt and other bis-salicylaldehyde-imine cobalt derivatives, bis-histidine cobalt(II) and related cobalt ( II) Amino acid complexes, iron(II) dimethylglyoximate and nickel(II) dimethylglyoximate.

Complexes of the formula K ₂ Zn ₃ [Fe(CN) ₆ ] ₂ ·xH ₂ O, where certain values of the variable x correspond to complexes that produce permanent pores upon removal of water.

2. Zeolite:

Octahedral NaX Zeolite

Octahedral NaY Zeolite

VPI-5 Zeolite

The coated particles 1 of the present invention are applicable in various fields. The coated particle 1 is adapted to absorb one or more substances from a selected environment, adsorb one or more substances from a selected environment or release one or more substances such as active agents distributed in a matrix.

With regard to absorption, the coated particles can be used to harvest products or remove waste during biological or chemical reactions, to carry catalysts in those processes, to remove toxins, antigens or waste in medical applications, to name a few.

With regard to adsorption, the coated particles are useful as chromatographic media and gas adsorbents.

With regard to release, the coated particles can be used for controlled release of medicaments such as anticancer agents or phototherapy agents or cosmetics. The active agent can be distributed in the matrix for release upon triggered release. For example, pharmaceutical or biologically active substances can be distributed in the matrix.

When these microparticles are used for drug delivery or for entrapment in proteins or polypeptides (especially receptor proteins), it may be advantageous to have a synthetic or semi-synthetic inner matrix designed to closely mimic the physicochemical properties of natural biofilms from living cells . This is important eg for proper action of receptor proteins or other membrane components or to facilitate assimilation of the inner matrix in drug delivery to native biofilms. Physicochemical properties that may be important in this regard include bilayer stiffness (a measure of bending resistance), bilayer fluidity (a measure of microviscosity inside the bilayer), acyl chain length and bilayer thickness, as lipid acyl chains Order parameter as a function of position, surface charge density, presence or absence of separate lipid domains of different composition within the bilayer, bilayer curvature and monolayer curvature (for a discussion of the relationship between these two curvatures see H.Wennerstrom and D.M. Anderson, in Statistical Thermodynamics and Differential Geometry of Microstructured Materials, Eds.H.T.Davis and J.C.C.Nitsche, Springer-Verlag, 1992, p.137), cholesterol content, carbohydrate content and lipid:protein ratio. These parameters can be tuned to a large extent in artificial systems, namely ultrastructural liquid or liquid crystalline phases, by appropriate choice of composition. For example, adding amphiphiles, especially fatty alcohols, can reduce bilayer stiffness; adjusting the ratio between uncharged lipids (such as lecithin) and charged lipids (such as phosphatidic acid) can tune the bilayer charge. Furthermore, the addition of cholesterol is important for the action of various membrane proteins. Lamellar phases, inverse bicontinuous cubic phases, L3 phases and to a lesser extent inverse hexagonal phases are particularly suitable for this method. Thus, the particles of the invention (inner matrix being such a phase with coordinated physicochemical properties for the incorporation of proteins or other biomolecules) may be very valuable in pharmaceuticals, clinical assays, biochemical research products, and the like.

For membrane proteins generally critically dependent on the bilayer environment to function properly and even maintain proper morphology, the present invention (especially with the coordinated bilayer properties as described above) may be excellent and very applicable matrix. Examples of membrane proteins include proteins such as protease A, amyloglucosidase, enkephalinase, dipeptidyl peptidase IV, γ-glutamyl transferase, galactose, neuraminidase, α-mannosidase, cholinesterase, aromatase, surfactin, ferrochelatase, spiralin, penicillin-binding protein, microsomal glycotransferase, kinase, bacterial outer membrane protein, and histocompatibility sex antigen.

Given the requirements for drug delivery in cancer therapy, the advantages and flexibility of the present invention make it particularly attractive for the delivery and release of antineoplastic agents, examples of which are as follows:

anticancer drug

Alkylating agent

Alkyl sulfonates - busulfan, propanesulfate, sulfonylsulfonate,

Aziridines-benzyltepa, carbaquinone, midapide, urethaneimine,

Aziridines and Methylmelamines - Hexamethylmelamine, Triethylenemelamine, Triethylenephosphoramide, Triethylenethiophosphoramide, Trimethylolmelamine,

Nitrogen mustards-chlorambucil, naphthalene mustard, cyclophosphamide, estramustine, ifosfamide, nitrogen mustard, oxambucil hydrochloride, phenylalanine mustard, new nitrogen mustard, phenylacetate mustard Cholesterol ester, pine mustard, cyclophosphamide, uracil mustard,

Nitrosoureas-Carmustine, Chlorurecin, Fortemidine, Cyclohexylnitrosourea, Pyrimidylnitrosourea, Reynolds mustard,

Others - Dacarbazine, Mannitol Mustard, Dibromomannitol, Dibromodulcitol, Propiperazine Bromide,

Antibiotics-Actacinomycins-actinomycin F1, anisenomycin, nitrogen serine, bleomycin, Cactinomycin, carmine, carcinophilic mycin, chromomycin, dactinomycin, daunorubicin, 6 -Diazo-5-OXO-L-norieucine, Adriamycin, Epirubicin, Mitomycin, Mycophenolic Acid, Nogamycin, Olivomycin, Pelemycin, Plicamycin, Porfiromycin, Puromycin, Streptomycin, Streptozotocin, Tubercidin, Hydroxybutyryl Leucine, Neocarcinstatin, Zorubicin,

antimetabolite

Folate analogues - Metfolate, Methotrexate, Pteroyltriglutamate, Trimetrexate,

Purine Analogues - Fludarabine, 6-Mercaptopurine, Thiamethoprine, Thioguanine,

Pyrimidine Analogues - Cyclocitidine, Azacytidine, 6-Azauridine, Carmofur, Cytarabine, Doxifluridine, Enoxabine, Fluoxuridine, Fluorouracil, Fufluorouracil,

Enzymes - L-asparaginase,

Others-Acetyglucuronate, Amsacridine, Bestrabucil, Bishanqun, Carboplatin, Cisplatin, Phosphatamine mustard, Colcemid, Diacrine, Ilonide, Hydroxycarbazole Acetate, Epoxyglycerin Ether, etoposide, gallium nitrate, hydroxyurea, interferon-ot, interferon-P, interferon-y, interleukin-2, fenugreek, lonidamine, imihydrazone, mitoxantrone , monopiperamin, diamine nitroacridine, Pentostatin, methamin, piramycin, podophyllic acid, 2-ethylhydrazide, procarbazine, PSK09, propylimine, cisophyllin, Spiral germanium, paclitaxel, teniposide, fine spirosporine, triimine quinone, 2,2′,211-trichlorotriethylamine, urethane, vinblastine, vincristine, vindesine .

Antineoplastic Drugs (Hormones)

Male hormones-Dimethyltestosterone, Methylandrostanone Propionate, Cyclothiosterol, Cyclopentylthioandrostane, Testolactone,

Anti-adrenaline-amino-dragon, o-to-didi, trilosteine,

Andandrogens-Fretam, Nilutamide,

Antiestrogens - Tamoxifen, Toremifene,

Estrogens - diethylstilbestrol diphosphate, hexestrol, estradiol polyphosphate,

LH-RH analogs - Buserelin, Sexrelin, Leuprolide, Triptorelin,

Progestins - chlormadinone acetate, medroxyprogesterone, megestrol acetate, melengestrol,

Antineoplastic Drugs (Radiation Sources)

Americium, Cobalt, ¹³¹ I-Ethiodized Oil, Gold (Radioactive, Colloidal), Radium, Radon, Sodium Iodide (Radioactive), Sodium Phosphate (Radioactive),

Antitumor Adjuvant

Folic Acid Supplement - Folinic Acid,

Uroprotective - Sodium mercaptosulfonate.

Other examples of uses of the coated particles of the present invention include:

1. Paints and inks, including microencapsulation of pigments; cationic loading of pigments (where the dependence on pH may be important); fillers and texturing agents for non-aqueous paints;

2. Paper, including microencapsulated opacifiers (also in coatings); pressure-sensitive ink microcapsules for carbonless copy paper;

3. Nonwovens, including additives attached to fibers throughout the process;

4. Agriculture, including controlled release of pheromones for insect control (otherwise some pheromones are volatile or unstable in the environment if not encapsulated); controlled release of chemical sterilization agents and growth regulators for insects (otherwise most of which are unstable in the environment); controlled release of other pesticides (important regardless of temperature); controlled release of herbicides; encapsulation of plant growth regulators ethylene and acetylene (otherwise they are volatile); Taste improvers (such as capsaicin) that deter mammalian pests; release of nutrients and fertilizers;

5. Environment and forestry, including controlled release of aquatic herbicides for weed control; controlled release of other herbicides; controlled release of nutrients in marine organism farming; soil treatment and release of nutrients; encapsulation of chelating agents and release (e.g. for heavy metal pollutants); deposition of actives and control of environmental hazards (i.e. by targeted release of crystal coatings and/or viscous cubic phases); encapsulation of hygroscopic or other (e.g. urea and chlorinated Sodium) "seed" agents for weather control;

6. Vaccines, including HIV gag, gag-pol transfection of cells as examples; adjuvants for proper presentation of antigens or antibodies;

7. Nuclear medicine, including the separation of two (otherwise mutually destructive) radionuclides into distinct particles for the treatment of cancer;

8. Cosmetics, including antioxidants, anti-aging skin creams; separation of two components of anti-acne drugs; sunscreen skin care lotions with encapsulated prostaglandins and vitamins; encapsulation of fat-soluble vitamins, oxidation-sensitive vitamins, and mixed vitamins Encapsulation of volatile essences and other fragrances; Encapsulation of volatile essences for sniffing advertisements; Encapsulation of volatile make-up removers or other cosmetics for flake formation; Encapsulation of solvents for use in nail polish removers (or nail polish itself); aerosol particles containing encapsulated hair dye; sanitary napkins containing encapsulated deodorant;

9. Veterinary medicine, including controlled release of volatile anti-flea compounds; encapsulated feed additives for ruminants; encapsulation of antibacterial agents and insecticides in animal husbandry;

10. Teeth, including controlled release toothpaste components, especially hydrolytically unstable anti-tartar compounds; delivery of oral anti-cancer compounds (photophyrin);

11. Polymerization catalyst in a can (single package) resin system;

12. Household products, including controlled-release air fresheners, fragrances; controlled-release insect repellents; detergents (such as encapsulated proteases); other decontamination applications; softeners; fluorescent whitening agents;

13. Industry, including the encapsulation of volatiles such as phosphine and ethylene dibromide for fumigation and storage products; catalytic particles; activated carbon particles for adsorption and purification;

14. Polymer additives, including polymer additives used to prevent wires, paper cards, etc. from being bitten; impact modifiers; colorants and opacifiers; flame retardants and smoke inhibitors; stabilizers; fluorescent whitening agents;

Current polymer-based additive encapsulation limitations include low melting point (during processing), polymer-polymer incompatibility, particle size limitations, optical clarity, etc. Certain polymer additives for lubricating polymers are based on waxes, which have the disadvantage of very low melting points (except for some very expensive synthetic paraffin waxes).

15. Processing of food and beverages, including encapsulation of (volatile) flavors, aromas and oils (e.g. coconut, mint); encapsulation of vegetable oils in cattle feed; encapsulated enzymes for fermentation and purification (e.g. beer brewing diacetyl reductase in phospholipids); encapsulation as an alternative to tin plating to improve the longevity of frozen foods; microencapsulated tobacco additives (flavoring); pH-triggered buffers; Activated carbon removes impurities and decolorizes;

16. Photography, including fine-grained films with dispersions of photoreactive submicron particles; instant films, due to the high optical clarity (and thus higher transmittance) and shorter diffusion times of submicron dispersions; microcapsules of light-processing agents encapsulation;

17. Explosives and propellant fuels, including liquid and solid propellant fuels and explosives, are used in encapsulated forms; moreover, water is also encapsulated in solid propellant fuels as a temperature moderator;

18. Research, including microcapsule packed towers in extraction and separation; biochemical assays, especially in pharmaceutical research and screening;

19. Diagnostics, including encapsulated labels for angiography and radiography and clinical assays involving environmentally sensitive proteins and glycolipids.

The ideal trigger to initiate release of the active agent or to initiate absorption is:

I. Release by dissolution or rupture of the coating

A. Connotation variables

1.pH

2. Ionic strength

3. Pressure

4. Temperature

B. Extensive variables or others

1. Dilution

2. Surfactant effect

3. Enzyme activity

4. Chemical reactions (non-enzymatic)

5. Coordination with the target compound

6. Current

7. Radiation

8. Time (i.e. slow dissolution)

9. Shear (effect of critical shear rate)

II. Release or absorption through pores in the coating, circumventing the need for dissolution or rupture of the coating

1. Selectivity of compound size by pore size

2. Selectivity of compound polarity by pore wall polarity

3. Selectivity of compound ionization degree through pore wall ionization degree

4. Selectivity of compound shape by pore shape

5. Selectivity of coated porous inclusion compounds according to certain compounds or ionic forms (this is generally a combination of the above four effects).

In a preferred embodiment, the coated particles can be prepared as follows:

1. providing an amount of a substrate comprising at least one chemical species having a first moiety capable of forming a non-lamellar crystalline material when reacted with a second moiety, and

2. contacting said substrate with a fluid containing at least one chemical species having said second moiety to react said first moiety with said second moiety while finer said substrate by applying energy to said substrate into particles.

Alternatively, the coated particles can be prepared as follows:

1. providing an amount of matrix comprising a non-lamellar crystalline material in solution therein, and

2. The non-lamellar crystalline material is made insoluble in the matrix while subdividing the matrix into particles by applying energy to the matrix.

In a general method, compound A, which forms a non-lamellar crystalline material when reacted with compound B, is added to a certain amount of matrix, and a fluid (typically an aqueous solution, commonly referred to as the "top solution") containing compound B ) overlying the matrix, contact between Compound A and Compound B causes crystallization at the inner/outer interface while application of energy such as sonication dislodges particles coated with non-lamellar crystalline material into the fluid . This method of the present invention is uniquely well suited for producing aqueous dispersions of coated particles with coatings of substances of low water solubility, i.e. preferably less than about 20 g/L water, even more preferably less than about 10 g/L water . In these methods it is very advantageous to dissolve (ie not merely disperse or suspend) component A in the matrix before contacting B and commencing sonication, in order to finally obtain a homogeneous particle dispersion. As mentioned earlier, this is one of the reasons for the importance of the ultrastructural matrix having hydrated domains to allow the dissolution of Compound A, which in most cases is only soluble in polar solvents (in addition to requiring active agents, especially biological Dissolution optimization in ). In particular, reactions that produce non-layered inorganic crystalline precipitates are generally most convenient and efficient to perform in aqueous media, and reactions that produce non-layered organic crystalline precipitates from dissolved precursors are often most conveniently and efficiently chosen as pH-induced, desired Protonation or deprotonation reactions of soluble salt forms of non-lamellar crystalline topcoat species where water (or aqueous microdomains) is the obvious medium.

Alternatively, cooling temperatures, crystallization accelerators, or electrical current can be used to induce crystallization.

In addition to sonication, other standard emulsification methods can also be used as energy input. These include microfluidization, valve homogenization [Thornberg, E. and Lundh, G. (1978) J. Food Sci, 43: 1553] and paddle agitation, among others. Ideally, a water-soluble surfactant, preferably an amphiphilic block copolymer with a molecular weight of several thousand Daltons such as PLURONIC F68, is added to the aqueous solution to stabilize the coated particles from agglomeration as they form. The surfactant is also used to enhance sonication if sonication is used to promote particle formation.

Many of the non-lamellar crystalline-coated particles described in the examples reported herein were prepared by a process in which two or more reactants were present at the interface between the external solution and the liquid or liquid-crystalline phase of the ultrastructure The reaction forms a precipitate which forms the outer coating. Another method with important similarities and important differences to this method is that in which the substance to form the coating (referred to as substance A) is dissolved in a liquid phase substance or a liquid crystal phase substance, by changing one of the substances One or more conditions such as increasing temperature (but also another change such as reducing pressure, adding volatile solvents etc.) promote this dissolution. This change must be reversible, so that when the conditions are reversed (such as temperature decrease, pressure increase, solvent evaporation, etc.), the system returns to the ultrastructure of liquid or liquid crystal phase material and non-lamellar crystalline material A Two-phase mixture. The energy input is applied before the non-layered crystalline substance A has time to become large crystals, this may be through the application of ultrasound or other emulsification methods. This leads to the detachment of particles coated with non-layered crystalline material A.

In the case of using temperature, the solubility of Compound A in the liquid phase material of the ultrastructure or the liquid crystal phase material of the ultrastructure must change with temperature, and the greater the slope of the solubility versus temperature curve, the higher the temperature required for this method. The increment is smaller. For example, the solubility of potassium nitrate in water varies greatly with temperature.

The basic difference between the precipitation reaction method and this type of method is that in this type of method, only one compound (A) is required in addition to the inner matrix of the ultrastructure. In the precipitation reaction method, at least two compounds are required, component A in the ultrastructural phase, and component B initially in the outer phase (the "supernatant solution") overlying said ultrastructural phase . Component B in this case is generally simply a suitably selected acid or basic component. This is used to point out the similarity between the two approaches, in that the presence of component B in the external phase can be considered the "condition" (especially the pH in the acid/base case) that causes crystallization of A; A is dissolved, which is reversible by the acidic pH conditions imposed by the presence of the external phase. Perhaps the most important difference between the two approaches is whether or if a change in conditions occurs that causes A to crystallize (as in the A/B precipitation reaction) only when or if the external phase ("supernatant solution") contacts the ultrastructural phase ), or whether it occurs simultaneously (as in temperature-induced crystallization) throughout the bulk of the ultrastructural phase.

A combination of the above-mentioned A/B reaction method and temperature method can also be used. Typically in this approach, the compound desired as a particle coating is incorporated into the matrix in two chemical forms. The first is the chemical form of the final coating, typically the free acid (free base) form of the compound, which dissolves only at elevated temperatures and is insoluble in the matrix at the temperature at which particles are formed. The second is the precursor form, typically the salt form prepared by reacting the free acid with a base such as sodium hydroxide (or the free base form with an acid such as hydrochloric acid), even at the temperature at which the particles are formed Also soluble in the matrix. For example, in the case of a benzoic acid particle coating, both benzoic acid and sodium benzoate are added to a matrix, which is a matrix that does not dissolve benzoic acid at ambient temperatures but does so at higher temperatures. The top layer solution contains the components required to convert the precursor into the final coating form, such as hydrochloric acid in the case of sodium benzoate. When heating (so that both forms are substantially dissolved) followed by cooling, covering the overlying solution, sonicating the system, or applying energy, the formation of coated particles will involve cooling-induced precipitation and reaction-induced formation of coating crystals and There are two methods of precipitation. This has the advantage that providing two sources of crystalline coatings can result in particle coverage earlier than a single method, thus increasing protection against particle fusion (and possibly resulting in a more uniform particle size distribution), and more efficiently at lower energy input requirements. form particles etc.

Other methods that can be used to prepare coated particles of the present invention are:

A. Electric crystallization,

B. put into crystal seed (be supersaturated solution in matrix, put into crystal seed in external phase),

C. Acceleration (using a supersaturated solution in one phase and a crystallization accelerator in the other phase),

D. Removal of inhibition (using a supersaturated solution in one phase and seeding the other phase), or

E. Time method (slow growth of crystals from supersaturated solution in internal phase).

To form many desired topcoats, including nearly all inorganic coatings, one (and often both) of the reactants are inevitably soluble only in water or other polar solvents. In particular, most of the salts used in these precipitation reactions are only soluble in highly polar solvents. Also, for the matrix material to be dispersible in water according to the present invention, it seems to be a highly desirable (if not absolute) condition that the internal phase material be substantially insoluble in water, otherwise some or all of the material will dissolve in the supernatant solution rather than disperse in the in. Thus, to form these coatings, the substrate must satisfy the following two conditions:

Condition 1: it must contain aqueous (or other polar solvent) domains; and

Condition 2: It must be of low water solubility, i.e. low enough (or have sufficiently low dissolution kinetics) that the process of particle generation from the phase (typically 5 to 100 minutes to disperse the entire material into particles) does not occur Significant phase dissolution, as this would significantly reduce production efficiency thereby reducing the overall profitability of the process.

These two conditions are almost in opposite directions, and it is rare to find a system that satisfies both. Ultrastructural liquid phase species and liquid crystalline phase species (of the trans or lamellar type) are a few of these very few systems.

In some cases it may be advantageous to incorporate one or more components of the ultrastructured liquid or liquid crystalline phase into the supernatant solution, sometimes in appropriate amounts. Indeed, the presence of a surfactant-rich liquid phase with an ultrastructure in the supernatant solution may be advantageous. In particular, this may occur when the matrix phase is not in equilibrium with water (or a dilute aqueous solution) but with another liquid or liquid crystalline phase such as a micellar phase or even a lamellar phase of low viscosity. Thus, as "fluid" referred to in the general description of the process given above, this phase or this phase to which additional components such as reactant B and/or amphiphilic block copolymer stabilizer have been added may be used. kind of phase. In this case, any incorporation of this upper phase into the microparticles will not be complicated, since said upper phase can (generally will) be chosen to be in equilibrium with the matrix phase (except for the exchange of active ingredients between the two substances, This has some causality but usually not important). After the coated particle is formed, it will initially be dispersed in this upper "solution", from which the continuous external phase will become another medium such as water, saline, buffer, etc., by filtration or dialysis.

The following examples illustrate but do not limit the invention.

Example

Of the following examples, Examples 14, 15, 16 and 34 illustrate systems with coatings composed of physically robust inorganics such as copper ferrocyanide and calcium phosphate, which allow intact particles to Stability such as during pumping of the coated particle dispersion (for example for circulation or transport). These inorganics are also low in water solubility, making them a potential advantage in applications requiring release of particle coatings by strong shear while preventing release from dilution with pure water. Examples of such applications are rodent deterrents such as capsaicin or rodent toxins encapsulated in the coated particles of the present invention, injecting particles into electrical wires, corrugated boxes, and other products that require protection from rodent bites, rodents The gnawing action of the will result in the release of active blockers or toxins. Low water solubility prevents premature release of barriers due to moisture.

A strong organic that provides the coating and is also of low water solubility is ethylhydrocupreine, as in Examples 17 and 33, an additional feature of this compound is that it has an extremely bitter taste and is not effective in rodent-impeding applications. has additional hindrance.

Examples 1, 2, 3, 6, 7, 8, 9, 10, 17, 18, 19, 20, 23 and 33 provide low water solubility at neutral pH but become acidic or basic with pH ( Examples of coatings with significantly increased solubility, depending on the compound. This can produce coated particles that are of great value eg in drug delivery where coatings that require preferential release, such as enteric release, in specific pH ranges. Or this coating will be released (allowing release of the antimicrobial compound) at the active site of the bacteria (where the pH is typically acidic). Or a release coating at a particular pH could release a pH-stable compound or buffer system, such as in microparticles designed to control the pH of water in swimming pools.

Example 4 gives examples of particles coated with silver iodide, which provide properties that are very suitable as cloud-seeding agents, because silver iodide coatings are known to have a cloud-seeding effect, the surface area provided by the shape and size of the particles and surface morphology can enhance the effect of silver iodide. This should be of commercial interest because silver compounds are expensive, in which case the inexpensive interior of the liquid crystal can act as a filler and will provide the same or greater seed potential at a fraction of the cost of simple silver iodide. A similar increase in effect due to increased surface area may be beneficial for the use of the particles as a local anesthetic for the mucosa, enhanced by a proper balance of lipids and active anesthetic hydrophobes (eg lidocaine) within the particle.

Example 5 demonstrates that compounds such as sulfides and oxides can be used as coatings for coated particles of the invention even when they require gaseous reactants to form. This compound is known not only to be a high stiffness material but also to have excellent chemical resistance, enabling such coated particles to be used in applications where the particles will encounter harsh chemical and physical conditions (such as when it is desired to use these particles as polymer additives). ) or have significance in processes involving high shear such as the impregnation of dye-containing particles in nonwovens.

Examples 12 and 13 demonstrate the use of highly water soluble compounds as coatings, which are valuable in applications requiring rapid and convenient release of the coating by dilution with water alone. For example, a spray system combining two streams (one containing the dispersion and the other water) can provide an aerosol in which a coating of particles suitable for preventing agglomeration prior to spraying will dissolve after spraying while the particles have Disperses in aerosol form - so to speak. Since this dissolution can expose, for example, the interior of the cubic phase of the very sticky ultrastructure, the particles can be used to adhere, for example, to crops or to bronchial linings and the like. The loading of capsaicin in Examples 12 and 13 is potentially valuable in making the product resistant to rodents, for example, after deposition of sticky aerosol particles on crops, since rodents are generally strongly attacked even at very low concentrations. The taste of capsaicin under the repels.

In the following examples, unless otherwise stated, all percentages are percentages by weight. The amounts of the components used in the following examples can be varied as desired, as long as the relative amounts are the same as in the examples; therefore, these amounts can be scaled up to the required amounts, taking into account of course that scaling up to larger amounts requires larger equipment.

In the following examples, unless otherwise specified, the outer coating layer of the coated particles includes non-lamellar crystals, and the inner core includes at least one ultrastructure liquid phase and at least one ultrastructure liquid crystal phase. Or a matrix composed of at least one ultrastructured liquid phase and at least one ultrastructured liquid crystal phase.

Example 1

This example illustrates that a wide range of active compounds, including compounds of importance in medicine and biotechnology, can be incorporated into the non-lamellar crystalline coated particles of the invention.

Dissolve 0.266 g of sodium hydroxide in 20 ml of glycerin, aiding dissolution with heat and stirring. An equimolar amount (ie 1.01 g) of methylparaben was then dissolved (also under heating). From this solution, 0.616 g was taken and mixed with 0.436 g lecithin and 0.173 g oleyl alcohol in a test tube. At this point the active ingredients (or reagents) shown below are incorporated, and the solution is thoroughly mixed to form an ultra-structured liquid crystalline phase substance in which the active ingredient is distributed. 0.062g of PLURONIC F-68 (polypropylene oxide-polyethylene oxide block copolymer surfactant purchased from BASF) and 0.0132g of acetic acid were dissolved together and added to the test tube as a mixture containing the active agent. A layer of solution on top of the above solution yields the "top solution". The test tube containing the liquid crystal mixture and the upper layer solution was immediately shaken vigorously and sonicated for 3 hours in a small bench-top ultrasonic oscillator (Model FS6, manufactured by Fisher Scientific). The resulting dispersion exhibited a high loading of methylparaben-coated particles approximately 1 micron in size when viewed with an optical microscope.

Example 1A incorporates 2.0 wt% salicylic acid (based on the weight of the core of liquid crystal phase material) as the active agent.

Example 1B incorporates 2.0 wt% vinblastine sulfate (based on the weight of the inner core of the liquid crystal phase material) as an active agent.

Example 1C incorporates 2.4 wt% thymidine (based on the weight of the core of liquid crystalline phase material) as the active agent.

Example 1D incorporates 1.6 wt% thyrotropin (based on the weight of the core of liquid crystalline phase material) as the active agent.

Example 1E incorporates 2.9 wt% anti-3',5'-cyclic AMP antibody (based on the weight of the inner core of the liquid crystal phase material) as the active agent.

Example 1F incorporates 2.0 wt% L-thyroxine (based on the weight of the core of the liquid crystal phase material) as the active agent.

These particles, such as particles with coatings whose solubility increases significantly with increasing pH, are suitable for drug delivery, as the increase in pH results in efficient delivery to the lower GI tract as it moves from the stomach to the intestine along the GI tract, enabling delivery over time. The rate is more uniform.

Example 2

This example demonstrates the long-term stability of the particle dispersions of the invention.

0.132g of amino acid D, L-leucine was dissolved in 2.514g of 1M hydrochloric acid to form a leucine hydrochloride solution. The solution was dried on a hot plate under a stream of air, but not to complete dryness; drying was stopped when the weight reached 0.1666 g, which corresponds to the addition of 1 molar equivalent of HCl to leucine. 0.130 g of this compound was added to 0.879 g of an ultrastructured inverse bicontinuous cubic phase material prepared by mixing sunflower oil monoglycerides and water, centrifuging and removing excess water. Mix 1.0 g of 1M sodium hydroxide with 3 g of water to prepare the upper layer solution. All water used was triple distilled. The supernatant solution was overlaid on the cubic phase, the tube was sealed and sonicated to form a milky white dispersion of leucine-coated microparticles.

A similar dispersion was prepared using PLURONIC F-68 as a stabilizer. 0.152g of leucine hydrochloride was added to 0.852g of the inverse bicontinuous cubic phase material of the above ultramicrostructure, and the upper phase consisting of 0.08gF-68, 1.0g of 1M sodium hydroxide and 3.0g of water was covered on the ultramicrostructure. The structure of the inverse bicontinuous cubic phase material was sonicated. A dispersion of milky leucine-coated microparticles was also formed, at which point the F-68 amphiphilic block copolymer surfactant coated the outer (leucine-based) surface of the particles.

As a comparative test to show the necessity of leucine for the formation of crystal-coated particles, 1.107g DIMODAN LS (hereinafter "sunflower monoglycerides") was mixed with 1.000g water to form an ultrastructured anti-bicontinuous cubic phase material. The 0.08g PLURONIC F-68 was added to 4.00g of water to prepare the upper layer solution. The same as above for the preparation of the dispersion with leucine, the upper layer solution was covered on the ultrastructured inverse bicontinuous cubic phase material, the test tube was sealed and sonicated. In this case, essentially no particulates were formed; even after several hours of sonication under the same conditions as for the leucine test, the ultrastructured inverse bicontinuous cubic phase material remained in macroscopic chunks.

This dispersion of coated particles of the present invention showed no signs of irreversible flocculation over a period of twelve months on regular inspection. With even light agitation, it showed no signs of irreversible flocculation over several weeks. Without agitation, signs of flocculation were shown, but with gentle shaking for 5 seconds or more, all flocculation was reversed. Observation of a drop of dispersion in an Edge Scientific R400 3-D microscope at 1,000X magnification (100× objective, oil immersion, transmitted light) revealed a very high load of submicron particles.

Particles with relatively weak organic coatings such as these are useful eg in acne lipids, where active substances such as dichlorophene may be incorporated and the shearing associated with applying the substance to the skin will release the coating.

Example 3

In this embodiment, paclitaxel is incorporated at a content of 0.5% of the inner core. The particle coating was leucine, which has been shown in other examples herein to provide long-term stability.

4 mg paclitaxel (dissolved in 2 ml tert-butanol) was mixed into the ultrastructural inverse bicontinuous cubic phase material containing 0.280 gm lecithin, 0.091 gm oleyl alcohol and 0.390 gm glycerol to prepare the ultrastructural inverse bicontinuous cubic phase containing paclitaxel phase material; upon evaporation of butanol under argon, an ultrastructured inverse bicontinuous cubic phase material is formed, which is viscous and optically isotropic. The sample was centrifuged for 1 hour during which time no precipitation occurred. Optical isotropy was verified in polarized light microscopy. 0.241 g of leucine, 2.573 g of 1M HCl and 0.970 g of glycerol were mixed, then water and excess HCl were evaporated on a 50° C. hot plate under air flow, and dried for 3 hours to produce a glycerol solution of leucine hydrochloride. Then, 0.882 g of this leucine-HCl solution in glycerol was added to the ultrastructured inverse bicontinuous cubic phase material. Then 0.102g of PLURONIC F-68 was added to 4.42g of pH 5.0 buffered aqueous solution to prepare the upper layer solution. After covering the upper layer solution on the inverse bicontinuous cubic phase substance of the ultramicrostructure, sonicate for 2 hours to disperse the inverse bicontinuous cubic phase of the ultramicrostructure into particles.

Particles such as these can be used for the controlled release of the antineoplastic agent paclitaxel.

Example 4

In this example, the coating is silver iodide, which has the potential to produce grains suitable for photographic processes. Silver iodide is a bit special because although it is a simple salt (monovalent ions only), it has very low solubility in water.

The ultrastructured inverse bicontinuous cubic phase material was prepared by mixing 0.509 g DIMODAN LS (commercially available e.g. from Grinstedt AB, referred to herein as "sunflower monoglyceride"), 0.563 g triple distilled water, and 0.060 g sodium iodide . An upper layer solution was prepared by adding 0.220 g of silver nitrate, 0.094 g of PLURONIC F-68 and 0.008 g of cetylpyridinium chloride to 3.01 g of water. The overlying solution was then overlaid on top of the ultrastructured bicontinuous cubic phase material and sonicated for 1 hour to produce a microparticle dispersion. The particle coating is silver iodide, which has low solubility in water.

Example 5

In this example, cadmium sulfide was used as the coating. It is a non-layered crystalline compound whose physical properties change greatly when doped with a small amount of other ions. This example also demonstrates that a gas such as hydrogen sulfide gas can be used in the present invention to induce crystallization and particle formation.

An ultrastructured inverse bicontinuous cubic phase material was prepared by thoroughly mixing 0.641 g of DIMODANLS with 0.412 g of water, to which 0.058 g of cadmium sulfate hydrate was added. The mixture was then overlaid with 0.039 g of cadmium sulfide, and the tube was purged with argon and capped. Add 0.088g of PLURONIC F-68 and 1.53g of glycerol to 1.51g of 1M HCl, and then purge the solution with argon to prepare the upper layer solution. The supernatant solution was drawn into a syringe and added to the first test tube. Hydrogen sulfide gas could be smelled in the test tube upon addition and a pale yellow precipitate formed; this indicates the role of hydrogen sulfide gas in the production of cadmium sulfide (CdS) from cadmium sulfate. The system was sonicated to obtain a particle dispersion coated with cadmium sulfide.

Example 6

This example demonstrates that the crystalline coating (here leucine) essentially shields the interior from extragranular conditions. Any contact with zinc powder turned the methylene blue colorless in less than 1 second; here, the addition of zinc did not fade for about 24 hours. Although the color faded eventually, it was believed that this fade was only due to the action of the zinc on the leucine coating.

An aqueous solution of leucine hydrochloride was prepared by mixing 0.122 g of leucine with 1.179 g of 1M HCl and evaporating until about 1 g of solution remained. To this was added 0.922 g of sunflower monoglyceride and 10 drops of a very strongly colored aqueous solution of methylene blue. 0.497g 1M NaOH and 0.037g PLURONIC F-68 were added to 3.00g pH 5 buffer to produce a supernatant solution. Overlay the overlying solution and sonicate the system to form a particle dispersion. An aliquot of this dispersion sample was filtered to remove any undispersed liquid crystals and 0.1 g of 100 mesh zinc powder was added. (When the zinc powder is shaken with the methylene blue solution, the reduction of the zinc removes the blue, usually within about 1 second or nearly simultaneously). However, in the case of microencapsulated methylene blue produced by this method, the color disappeared over 24 hours and a white dispersion was finally obtained. Thus, although the interaction between zinc and leucine may disrupt the coating of these particles, the coating still substantially protects methylene blue from zinc, increasing the time required for zinc reduction of this dye by about 4 -5 orders of magnitude.

If particles such as these are used in products where it is necessary to keep two active ingredients separated from each other (such as the oxidation-sensitive antimicrobial compound diclofenac and the strong oxidation scavenger benzoyl peroxide), the test demonstrates that Feasibility of particles coated with leucine to prevent contact between the encapsulated compound and the extragranular environment.

Example 7

In this example, the leucine coating protects the methylene blue dye within the particles from contact with ferrous chloride, as is readily seen by an unexpected color change when ferrous chloride is added to the dispersion. This indicates that the coating is substantially impermeable to ions.

A glycerol solution of leucine hydrochloride was prepared by mixing 0.242 g of leucine, 2.60 g of 1M HCl, and 1.04 g of glycerol, and then drying on a 50° C. hot plate under air flow for 1.5 hours. The leucine-HCl solution, 0.291 g lecithin (EPIKURON 200 from Lucas-Meyer), 0.116 g oleyl alcohol and 0.873 g glycerol were mixed to prepare an ultrastructured inverse bicontinuous cubic phase material; a pinch of methylene blue was added to make it coloring. 0.042g PLURONIC F-68 surfactant was added to 4.36g pH5 buffer to prepare an upper layer solution, which covered the ultrastructured inverse bicontinuous cubic phase material, and the system was sonicated to produce a particle dispersion. To an aliquot of this dispersion was added 0.19 g of ferrous chloride (reducing agent). The absence of a color change indicates that methylene blue was encapsulated in the leucine-coated particles without contact with the iron compound, since the addition of ferrous chloride to methylene blue solutions usually turns the color blue-green (turquoise).

Similar to Example 6, this test demonstrates that an encapsulated compound such as methylene blue (which in this case is sensitive to reducing agents) can be protected from extragranular reducing conditions until the coating is released. This is applicable, for example, in electrochemical applications, where chemical release by the coating turns on the effect of applied electrical current.

Example 8

This example, when considered together with Example 1A and Example 10, demonstrates that the methylparaben-coated particles of the present invention can be produced by two entirely different methods: by thermal methods such as heat-cooling methods, or by chemical reactions Such as the acid-alkali method.

Mix 0.426g sunflower monoglyceride (DIMODAN LS) with 0.206g pH3 acidic water to produce an ultrastructured inverse bicontinuous cubic phase material, to which 0.051g methylparaben and a trace amount of methylene blue dye are added. The mixture was heated to 110°C, shaken, and placed on a vibrating mixer and immersed in water at 23°C for 5 minutes. Overlay 2 ml of 2% PLURONIC F-68 solution (acidified to pH 3 with HCl), seal the tube with a twist cap, shake the tube and then sonicate for 30 minutes. This produced a dispersion of microparticles coated with methylparaben.

Since this example, together with Example 10, demonstrates that particles coated with the same compound (in this case methylparaben) can be produced thermally or by chemical precipitation, this provides additional versatility, possibly in There is value in optimizing production efficiency and minimizing costs, for example in the large-scale production of microencapsulated pharmaceuticals.

Example 9

The ultrastructured inverse bicontinuous cubic phase material in this example is based on non-ionic surfactants generally licensed for the formulation of pharmaceuticals that produce liquid crystalline phase materials whose properties can be tuned by small temperature changes . For example, in acne lipids, this can be used to achieve detersive (cleaning) properties at application temperatures, but insolubility at formulation temperatures. Furthermore, since it is based on a blended mixture of two surfactants, and since its phase and properties depend sensitively on the ratio of the two surfactants, this provides a convenient and powerful means of controlling the properties of the core. Furthermore, this example produces a transparent dispersion. This is notable because even a small fraction of particles having a particle size greater than about 0.5 microns produces an opaque dispersion.

Mix 0.276g "OE2" (commercially available ethoxylated alcohol surfactant such as "Ameroxol OE-2" supplied by Amerchol, a division of CPC International, Inc.) with 0.238g "OE5" (commercially available A commercially available ethoxylated alcohol surfactant, such as "Ameroxol OE-5" supplied by Amerchol, adivision of CPC International, Inc.), and adding 0.250 g of water (including excess water) to prepare ultrastructural reflections Bicontinuous cubic phase material. To this was added 0.054 g of methylparaben and a trace of methylene blue dye. The mixture was heated to 110°C, shaken, and placed on a vibrating mixer and immersed in water at 23°C for 5 minutes. Overlay 2 ml of 2% PLURONIC F-68 solution (acidified to pH 3 with HCl), seal the tube with a twist cap, shake the tube and then sonicate for 30 minutes. This produces a dispersion of microparticles coated with methylparaben. Interestingly the submicron size of the particles results in transparent dispersions.

Example 10

This example demonstrates that methylparaben-coated particles can be produced by a heat-cool method in addition to the acid-base method of the previous examples. This example also demonstrates that a mixture of two phases can be dispersed.

Lecithin (EPIKURON 200, 0.418g) was mixed with 0.234g oleyl alcohol and 0.416g pH3 acidic water to obtain a mixture of ultrastructured inverse bicontinuous cubic phase material and ultrastructured inverse hexagonal phase material. 0.50 g was taken out therefrom, 0.049 g of methylparaben was added thereto, and mixed well. It was heated to 120°C, stirred while hot, and then heated to 120°C. Remove the test tube from the oven and immerse the test tube in cold water for 5 minutes. The twist cap was then removed, covered with 2 ml of 2% PLURONIC F-68 solution (acidified to pH 3 with HCl), the sample was agitated, shaken and finally sonicated. This produced a milky dispersion of microparticles coated with methylparaben. Observation in an optical microscope revealed microparticles with sizes in the range of 2-10 microns. Excess methyl paraben crystalline material was also observed.

This example demonstrates that a mixture of two co-existing ultrastructural phases can provide the interior of a microparticle. This could be valuable in, for example, controlled-release drug delivery, where a mixture of two phases (each loaded with drug) can be used to achieve the desired pharmacokinetics: for example, a mixture of inverse hexagonal and cubic The release of the phases follows different kinetics because of the different solid geometry of the pore space, and the resulting kinetics will be a combination of these two figures.

Example 11

This example demonstrates that an anhydrous particle interior can be created, eg, for the protection of water sensitive compounds.

The same procedure as in the preparation of Example 10 was followed, but glycerol (present in excess) was used instead of water in the preparation of the ultrastructured bicontinuous inverse cubic phase liquid crystalline material. The amount of each substance is: lecithin 0.418g, oleyl alcohol 0.152g, glycerin 0.458g and methyl hydroxybenzoate 0.052g. The result is a milky white dispersion of methylparaben-coated microparticles.

Protection of water-sensitive active compounds is valuable, for example, in oral health products incorporating hydrolytically labile active substances.

Example 12

In this example, capsaicin was incorporated into potassium nitrate-coated particles in which the ultrastructured inverse bicontinuous cubic species was based on an extremely inexpensive surfactant. The coating is easily removed by simply adding water - as in a crop-brush gun, the dispersion stream is combined with the water stream to aerosolize the liquid into droplets. Note the dual use of potassium nitrate as a fertilizer.

The nonionic surfactants "OE2" (0.597g) and "OE5" (0.402g) were mixed with 0.624g of water saturated with potassium nitrate. To this mixture was added 0.045 g of the active compound capsaicin (in pure crystalline form, obtained from Snyder Seed Corporation). Then 0.552 g of this mixture was taken out, 0.135 g of potassium nitrate was added, and the resulting mixture was heated to 80° C. for 5 minutes. Take 2% PLURONIC F-68 aqueous solution and saturate it with potassium nitrate to prepare the upper layer solution. The molten mixture was shaken to mix and then returned to the 80°C oven for 2 minutes. Immerse the test tube in water at 20°C for 5 minutes. At this time, cover the upper solution, stir the whole mixture with a spatula, cover, shake, and sonicate. The result is a dispersion of formazan-coated microparticles with the active ingredient capsaicin inside.

On diluting the dispersion with an equal volume of water, the coating dissolved (potassium nitrate has a high solubility in water at room temperature), which was manifested by rapid coagulation and coalescence of the particles into large clumps. Inside the particles are viscous liquid crystals, so in the absence of a coating, condensation and fusion take place.

The embodiment we are discussing here is a spray used on decorative plants and/or crops to deter animals from eating the leaves. We have had success in encapsulating the compound capsaicin, a non-toxic compound (found in red peppers and paprika) that produces a burning sensation in the mouth at concentrations in the few ppm range. Capsaicin has a commercial record as a deterrent for rodents and other animals.

Pure capsaicin is encapsulated within the cubic phase of particles coated with crystalline potassium nitrate (saltpeter). The extragranular external solution is a saturated aqueous solution of potassium nitrate, which prevents the coating from dissolving until it is diluted; diluting the dispersion approximately 1:1 with water results in near complete dissolution of the particulate coating. (This dissolution was filmed on videotape. Watching the videotape clearly sees the dissolution of the coating followed by fusion within the particles.)

Upon dilution and subsequent dissolution of the coating, the particle interior is exposed as a cubic phase with the following key properties:

A) It is insoluble in water;

B) it is extremely sticky; and

C) It has a very high viscosity.

These three properties taken together mean that uncoated cubic phase particles will adhere to plant leaves, and property A means that it will not dissolve even when it rains.

These three properties are also critical to the success of animal trials of the host cubic phase as a controlled release paste in the delivery of photodynamic therapy (PDT) agents for the treatment of oral cancer.

Capsaicin concentrations achieved in cubic phase particles were two orders of magnitude higher than in agents used to treat arthritis. Higher loads may be achieved, perhaps as high as 20%.

From a commercialization point of view, the components in this dispersion are extremely inexpensive and are all approved for food, topical applications, etc. In addition, potassium nitrate is a well-known fertilizer.

Example 13

This example uses capsaicin/potassium nitrate as the previous example, but here the ultrastructured inverse bicontinuous cubic species is based on lecithin, a basic compound in plant and animal life that is cheaply available. The ultrastructured bicontinuous cubic phase material is also stable over a wide temperature range, at least up to 40°C under normal weather conditions.

1.150 g soybean lecithin (EPIKURON 200) was mixed with 0.300 g oleyl alcohol, 1.236 g glycerin and 0.407 g potassium nitrate. To this was added 0.150 g of active capsaicin and the mixture was mixed thoroughly. Then, 0.50 g of potassium nitrate was added, and the resulting mixture was heated to 120° C. for 5 minutes. Take an aqueous solution of 2% PLURONIC F-68, saturate it with potassium nitrate, and prepare the upper layer solution. The molten mixture was stirred and then placed back into the oven at 120°C for 3 minutes. The tubes were immersed in cold water for 5 minutes, at which time the supernatant was covered, the entire mixture was stirred with a spatula, capped, shaken, and sonicated, then cycled 30 times alternating between shaking and sonicating. The result was a dispersion of potassium nitrate-coated microparticles containing about 5% of the active ingredient capsaicin inside. Excess potassium nitrate crystals were also present.

The application is similar to that of Example 12, but the internal use of lecithin allows better binding of the particle interior to the plant cell membrane, possibly resulting in better delivery.

Example 14

The shear resistance of copper ferrocyanide coated particles is demonstrated in this example.

Mix 0.296g of sunflower monoglyceride (DIMODAN LS) and 0.263g of 10% copper ferrocyanide aqueous solution to prepare ultrastructure reverse bicontinuous cubic phase material. Add 0.021g of copper sulfate and 0.063g of PLURONIC F-68 to 4.44g of water to prepare a supernatant solution. The supernatant solution was overlaid on top of the ultrastructured inverse bicontinuous cubic phase material, the tube was sealed with a twist cap, and the system was sonicated for 45 minutes. The result was a high concentration of particles (coated with copper ferrocyanide), about 3 microns in diameter. This method produces particles without the need for temperature excursions other than those associated with sonication that can be prevented using other forms of emulsification. Furthermore, no pH drift is required.

The copper ferrocyanide-coated particles were found to resist shearing well when a drop was viewed between a microscope slide and a cover slip; gentle finger pressure did not produce particles when the cover slip was pushed over the dispersion. Any apparent deformation or fusion. This is in contrast to, for example, particles coated with basic magnesium carbonate, where light compression leads to high deformation and fusion of the particles. These observations are consistent with the high stiffness of copper ferrocyanide.

Particles with a shear-resistant coating are valuable in applications requiring pumpable particles, and conventional polymer-coated particles are known to have lifetime limitations due to shear degrading the coating.

Example 15

In this example, capsaicin was incorporated into the interior of the crystal-coated particles of the invention at a rather high loading of 9% by weight. Mixing 0.329 g lecithin, 0.109 g oleyl alcohol, 0.611 g glycerin, and 0.105 g capsaicin (in crystalline form, obtained from Snyder Seed Corp., Buffalo, NY) produced an inverse bicontinuous cubic phase of the ultrastructure. To this cubic phase was added 0.046 g of copper sulfate. 0.563g of 10% potassium ferrocyanide aqueous solution was mixed with 2.54g of water to prepare the upper layer solution. The supernatant solution was overlaid on the cubic phase-copper sulfate mixture and the tube was sonicated for 2 hours. The reaction to form copper ferrocyanide is easily demonstrated based on the deep reddish-brown color of the compound. At the end of this time, the cubic phase was dispersed into copper ferrocyanide-coated particles. The coating is made of copper ferrocyanide, which is a strong substance with some selective permeability to sulfate ions. Since this coating is a solid crystal (as seen in Example 14), and capsaicin has a very unpleasant taste for rodents, these particles are suitable as rodent deterrents to prevent them from destroying corrugated boxes, agricultural plants, etc., especially in The gnawing action of the rodent opens the granules to expose the capsaicin to the animal's taste buds. The granules must be resistant to mild shear (such as during production of the granule edging bins or during deposition of the granules on plants).

Example 16

In this example, copper ferrocyanide-coated microparticles were produced in the same manner as in Example 14, but in this case antibodies were incorporated as active agents. Specifically, an anti-3',5' cyclic adenosine monophosphate (AMP) antibody was added as an active agent at an internal 1% by weight loading. The cubic phase was prepared by mixing 0.501 g sunflower monoglycerides with 0.523 g water. 0.048 g of potassium ferrocyanide was added to the cubic phase along with about 0.010 g of the antibody. Excess aqueous solution was removed by centrifugation. Add 0.032g of copper nitrate and 0.06g of PLURONIC F-68 to 3.0g of water to prepare the upper layer solution. After overcoating and sonication, a milky white dispersion of microparticles coated with copper ferrocyanide was obtained. Such particles can be used in biotechnological settings such as bioreactors, where the tough copper ferrocyanide coating is suitable for limiting the bioreactive antibody in the event of mild shear before the desired coating releases and becomes available. Released during cut conditions (e.g. in pressurized inlets).

Example 17

In this example, dihydronorquinine forms an extremely hard shell. In this example the acid-base method was used.

0.648 g of sunflower monoglyceride (DIMODAN LS) was mixed with 0.704 g of water to prepare an ultrastructured inverse bicontinuous cubic phase material. To this was added 0.084 g of norquinine hydrochloride and a trace of methylene blue. Add 1.01g of 0.1M sodium hydroxide and 0.052g of PLURONIC F-68 to 3.0g of water to prepare a supernatant solution. After covering the liquid crystal with the upper layer solution, the system was sonicated to obtain a dispersion of norquinine (free base)-coated microparticles. Most particles are less than 1 micron in size when viewed with an optical microscope.

Granules that retain their integrity under drying are suitable for example for the slow release of agricultural actives (herbicides, pheromones, insecticides, etc.), where dry climatic conditions can lead to premature release of less tolerant granules.

Example 18

Leucine-coated particles were produced in this example by the heat-cool method.

Mix 1.51g of sunflower monoglyceride (DIMODAN LS) with 0.723g of water to prepare ultrastructure inverse bicontinuous cubic phase material. To 0.52 g of ultrastructured inverse bicontinuous cubic phase material from this mixture was added 0.048 g of DL-leucine. The mixture was stirred well, heated to 80°C, and then cooled to room temperature by immersion in water. Immediately cover with 2% PLURONIC F-68 in water, shake the mixture, and sonicate. This produced a milky dispersion of leucine-coated microparticles.

The ability to prepare the same coating (leucine in this case) by thermal or acid-alkaline methods provides valuable production flexibility, since for example certain active substances (such as proteins) are very susceptible to denaturation with temperature but may be quite pH resistant, while other compounds may be temperature resistant but may hydrolyze at acidic or basic pH.

Example 19

This example shows that internal components can be protected from oxygen even when oxygen is bubbled into the external medium (here water).

An ultrastructured inverse bicontinuous cubic phase material (with excess water) was prepared by mixing 2.542 g sunflower monoglycerides with 2.667 g water. 0.60 g of an ultrastructured inverse bicontinuous cubic phase material was withdrawn therefrom. Then, 0.037 g of DL-leucine was mixed and dried with 0.497 g of 1M HCl, and 0.102 g of water was added to produce a solution of leucine hydrochloride, which was added to the 0.60 g of ultrastructure together with a trace of methyl red dye. in the anti-bicontinuous cubic phase of the material. The ultrastructured inverse bicontinuous cubic material is intensely yellow, but when deployed as a film it turns deep red within about 3 minutes due to oxidation. The upper layer solution was prepared by mixing 0.511 g of 1M sodium hydroxide, 0.013 g of PLURONIC F-68 and 2.435 g of water. The upper layer solution was covered on the liquid crystal, and sonicated to prepare leucine-coated particle dispersion containing methyl red. First check the aqueous solution of methyl red (with or without F-68), which rapidly changes from yellow to deep red when air is bubbled through. However, when air was bubbled through the microparticle dispersion containing methyl red, it was found that the color did not change from yellow, thus demonstrating that the methyl red was encapsulated within the microparticles to prevent oxidation of the methyl red.

Particles capable of protecting active compounds from oxygen such as these are suitable for protecting oxygen-sensitive compounds such as iron-supplemented foods, for example during long-term storage.

Example 20

In this example, the water substitute glycerol was used both in the inner ultrastructured inverse bicontinuous cubic phase material and as an outer (continuous) coating, thereby substantially excluding water from the dispersion.

Glycerin was used instead of water to prepare particle dispersion, soy lecithin and oleyl alcohol were mixed at 2.4:1, then excess glycerin was added, mixed and centrifuged. 0.70 g of this ultrastructured inverse bicontinuous cubic phase material was mixed with 0.081 g of methylparaben. The upper layer solution was prepared by adding 2% cetylpyridinium bromide to glycerol. Seal the ultrastructured inverse bicontinuous cubic phase substance-methylparaben mixture, heat to 120°C, mix well, reheat to 120°C, then immerse in cold water, at this time cover the upper solution, and then seal the test tube (with twist cap), harmonically processed. Microparticles coated with methylparaben in a continuous phase of glycerol were produced. Such glycerol-based dispersions are beneficial in the microencapsulation of water sensitive actives.

Using particulate dispersions such as these, hydrolytically unstable active substances encountered in a wide range of applications can be protected from contact with water, even after the coating has been released.

Example 21

Similar to the previous Example 6, where the encapsulated methylene blue was examined with zinc, but here the coating was potassium nitrate. In addition, the same dispersion was also examined with potassium dichromate.

0.667 g soybean lecithin, 0.343 g oleyl alcohol, 0.738 g glycerol, and a trace of methylene blue were mixed to prepare an ultrastructured inverse bicontinuous cubic phase material. To 0.469 g of this equilibrium phase was added 0.225 g of potassium nitrate. Add 2% PLURONIC F-68 to a saturated potassium nitrate aqueous solution to prepare an upper layer solution. This was overlaid on top of the liquid crystal and the system was sonicated until the liquid crystal dispersed into particles coated with potassium nitrate. The color of the dispersion is light blue. Two experiments were then used to demonstrate that methylene blue was encapsulated in microparticles to be protected. To about 1 ml of this dispersion was added about 0.1 g of finely powdered zinc: when the powdered zinc came into contact with methylene blue in solution, a loss of color occurred. After shaking, the mixture was subjected to a very short centrifugation, loading, centrifugation and removal from the centrifuge with a total time of about 10 seconds; interference. Very little, if any, reduction in blue color was found after treatment with zinc, indicating that the particulate coating prevents the methylene blue from contacting the zinc. Potassium dichromate was then added to another aliquot of the original light blue dispersion. This turned the color green with no sign of the purple-brown that would result from contacting methylene blue with potassium dichromate in solution.

The coated granules of this embodiment are characterized by the extremely low cost of the coating material potassium nitrate, which still protects the active compound from chemical degradation due to external conditions, making it potentially valuable, for example, in agricultural slow-release applications.

Example 22

This example provides examples of permselectively coated microparticles with clathrates. This particular clathrate (so-called Werner complex) has the property of maintaining porosity when the guest molecule is removed. Clathrate and clathrate coatings are beneficial as selective porosity coatings, where selectivity for release or absorption can be based on molecular size, shape and/or polarity.

First, 0.525 g of sunflower monoglyceride was mixed with 0.400 g of water to prepare an ultrastructured inverse bicontinuous cubic phase material. 0.039 g of manganese chloride (MnCl ₂ ) and 0.032 g of sodium thiocyanate were added thereto. 0.147 g of 4-picoline was added to 3.0 ml of 2% PLURONIC F-68 aqueous solution to prepare an upper layer solution. The supernatant solution was overlaid on the liquid crystal mixture, and the tube was sealed and sonicated. Thus, the anti-bicontinuous cubic phase material of the ultramicrostructure is dispersed into particles coated with manganese Werner complexes, namely Mn(NCS) ₂ (4-MePy) ₄ .

The coating in this example can be used to remove heavy metals from industrial streams. In this case, the coating can be porous crystals (called clathrates), which allow the ions of atoms to pass through the coating into the interior of the cubic phase, which due to its high surface charge density (using anionic surfactants or selective Higher chelating groups such as bispyridinium groups, etc.), counter-ions are absorbents with extremely high absorption capacity. The most likely permanent hole is best. The selectivity afforded by clathrate coatings prevents the inevitable decline in sorption capacity of traditional sorbents such as activated carbons and macroreticular polymers, as larger compounds compete with target heavy metal ions for available adsorption sites. Sorbent regeneration can be by ion exchange, leaving the particles and coating intact (the latter step is an example of release).

Example 23

In this example, coated particles having an outer coating comprising methylparaben and having a particular dye partitioned in an ultrastructural inverse bicontinuous cubic phase material were examined with cyanide, which when in contact with said dye Can change color. Since the cyanide ions are extremely small, the success of this test shows that the coating is impermeable even to very small ions.

An ultrastructured inverse bicontinuous cubic phase material was prepared by mixing 0.424 g sunflower monoglycerides with 0.272 g water. To this was added 0.061 g of methylparaben and a trace of the dye 1,2-pyridylazo-2-naphthol. A top layer solution of 1% cetylpyridinium bromide was prepared. Heat the liquid crystal in an oven at 120°C for 5 minutes, stir vigorously, reheat, and then immerse in cold water. At this time, cover the upper solution, seal the test tube, and put it into the sonic processor. The result was a dispersion of methylparaben-coated microparticles with an average particle size of about 1 micron. The dye is then demonstrated to be protected from the outside with cuprous cyanide. When cuprous cyanide is added to 1,2-pyridylazo-2-naphthol solution (with or without F-68), the color changes from orange to intense purple. However, when cuprous cyanide was added to an aliquot of the dye particle-containing dispersion, there was no color change, indicating that the methylparaben coating prevented the dye from contacting the cuprous cyanide. The diffusion time of the cuprous ions to the center of the 1 micron particle can be calculated to be on the order of seconds or less, which does not interfere with the color change of the coated unsealed particle.

Protection of active compounds from ionic contact with the external environment may be useful, for example, in drug delivery, especially of polyelectrolytes that can be complexed and inactivated by contact with multivalent ions.

Example 24

In this example, the cyanide ion test in the above example was repeated on potassium nitrate coated particles.

An ultrastructured inverse bicontinuous cubic phase material was prepared by mixing 0.434 g sunflower monoglycerides with 0.215 g water. To this was added 0.158 g of potassium nitrate and a trace amount of the dye 1,2-pyridylazo-2-naphthol. A 1% supernatant solution of cetylpyridinium bromide in saturated aqueous potassium nitrate solution was prepared. Heat the liquid crystal in an oven at 120°C for 5 minutes, stir vigorously, reheat, and then immerse in cold water. At this time, cover the upper solution, seal the test tube, and put it into the sonic processor. The result is a dispersion of potassium nitrate-coated microparticles. When cuprous cyanide was added to an aliquot of the dispersion of dye-containing particles, there was only a slight change in color, indicating that the potassium nitrate coating essentially prevented the dye from coming into contact with the cuprous cyanide.

The utility of these particles was similar to that of Example 23, but in this case the more economical coating of potassium nitrate was used.

Example 25

0.913 g soybean lecithin (EPIKURON 200), 0.430 g oleyl alcohol and 0.90 g glycerol (excess glycerol) were mixed to prepare an ultrastructured reverse bicontinuous cubic phase material. After thorough mixing and centrifugation, 0.50 g of the ultrastructured inverse bicontinuous cubic phase material was taken, and 0.050 g of dibasic sodium phosphate was added. Prepare an upper layer solution by adding 0.10 g of calcium chloride to 3 ml of an aqueous solution containing 2% PLURONIC F-68 and 1% cetylpyridinium bromide. After overcoating the liquid crystal-sodium phosphate mixture, the tubes were sealed and sonicated. The result is a dispersion of calcium phosphate coated microparticles. Calcium phosphate coatings are inherently valuable in the biological field because calcium phosphate is a major component of bones, teeth and other tissues.

Example 26

This example demonstrates that the magnesium carbonate coated particles retain their integrity when dry (ie when the outer aqueous phase is dried away). Therefore, it is possible to produce a dry powder while still having a water-rich liquid crystal phase inside.

Preparation of "Tung-Sorbitol Compound". First, the "tung-sorbitol compound" was prepared as follows:

110 g of tung oil (Chinese Tung Oil from Alnor Oil) was combined with 11.5 g of sorbitol in a reaction flask. The flask was purged with argon, sealed and heated to 170°C with magnetic stirring. Sodium carbonate (3.6 g) was added, and the mixture was stirred at 170°C for 1 hour. At this point 3.4 g of 3-chloro-1,2-propanediol were added and the mixture was cooled to room temperature. 75ml of the oily phase from this reaction was mixed with 300ml of acetone and the white precipitate was removed by centrifugation. Next, 18 g of water and 100 ml of acetone were added, and the mixture was centrifuged to remove the oily residue at the bottom. Then 44 g of water were added and the bottom phase was collected and discarded again. Finally, 20 g of water were added, at which point the oily residue at the bottom was collected and dried under a stream of argon. About 50 ml of tung fatty acid ester of sorbitol was produced, hereinafter referred to as "tung-sorbitol product".

Example 26A

0.110 g of "Tung-Sorbitol Product", 0.315 g of soybean lecithin and 0.248 g of water were mixed, thoroughly mixed and centrifuged to prepare an ultrastructural inverse bicontinuous cubic phase material. 0.085 g of potassium carbonate was added thereto. Then 0.118g of PLURONIC F-68 and 0.147g of magnesium sulfate were added to 5.34g of water to prepare a supernatant solution. The upper layer solution was covered on the liquid crystal, the test tube was sealed, shaken, sonicated for 2 hours, and then fully shaken again. The result is a milky white dispersion of microparticles coated with basic magnesium carbonate. Two parts water was added to one part dispersion to dilute it to dissolve excess inorganic crystalline material. A small drop of the dispersion was spread gently on a microscope slide and allowed to dry. After 10 minutes of drying, the extra-granular water was almost completely evaporated. Microscopic observations showed that the particles retained their shape and did not become unstructured droplets that would be observed when uncoated particles were dried in a similar manner (eg, a dry liquid crystal mixture turned into a liquid).

Example 26B

The dispersion produced in Example 26A was heated to 40°C. The internal phase at this temperature is an ultrastructured liquid L2 phase material as determined by phase behavior. The dispersion remained milky white and microscopically it also remained finely divided. Since this L2 phase contains oil, water, and surfactant (ie, lecithin), it is also an ultrastructured microemulsion.

Example 27

In this example, receptor proteins were partitioned within a matrix of ultrastructured inverse bicontinuous cubic phase material in the core of magnesium carbonate-coated particles, and the coated particles were then embedded in a hydrogel. Coatings on the particles can be used to protect the receptor protein during shipping and storage, and are then easily removed by washing before use. This example and Example 28 foreshadow the use of coated particles of the invention for eg affinity chromatography, where hydrogel beads are used in which coated particles of the invention are embedded.

Make 0.470g soybean lecithin (EPIKURON 200) mix with 0.183g " tung - sorbitol product) and 0.359g water. Add 0.112g potassium carbonate to it. Make it centrifuge several hours, remove excess aqueous phase. Press L. The experimental report described in Pradier and M.G.McNamee in Structure and Function of Membranes (ed.P.Yeagle, 1992, pp.1047-1106) prepares the torpedo nicotinic acetylcholine receptor preparation.In this preparation, 50 micrograms of receptor proteins contain In 50 microliters of lipids, the majority is dioleoylphosphatidylcholine (DOPC). (The rest are other membrane lipid components, such as other phospholipids, cholesterol, etc.). This amount of preparation is added to the super In a microstructured inverse bicontinuous cubic phase material-potassium carbonate mixture, stir the entire mixture lightly but long enough to ensure good mixing, as detected by the absence of birefringence. Mix 0.328g magnesium sulfate, 0.324g PLURONIC F-68 and 0.0722g of cetylpyridinium bromide was added to 20.02g of water to prepare a supernatant solution.5g of the supernatant solution was covered on the test tube containing the ultrastructure inverse bicontinuous cubic phase material loaded with the acceptor, and the test tube was sealed , shaken, and sonicated for 2 hours. Produced a dispersion of magnesium bicarbonate-coated receptor-containing microparticles, mostly in the 0.5 to 1 micron range.

The microparticles were then immobilized in a polyacrylamide hydrogel. Acrylamide (0.296g), methylenebisacrylamide (0.024g, as a crosslinking agent), ammonium persulfate (0.005g, as an initiator) and tetramethylenediamine (TMED, 0.019g, as a co-initiator agent) was added to the dispersion to polymerize the acrylamide into a cross-linked hydrogel in less than 30 minutes. Observation of a thin slice of this hydrogel under a microscope reveals a high concentration of microparticles, exactly the same as the original dispersion.

The hydrogel was further broken into small pieces of about 30 microns in size. This is achieved by pressing the hydrogel through a metal sieve with a mesh size of 40 microns.

Example 28

In this embodiment, the receptor protein is distributed in the inner core of the coated particle of the present invention, the coating is potassium nitrate, and then the coated particle is fixed in the hydrogel beads. The receptor-loaded beads were successfully tested for binding activity in a radioactive assay performed at UC Davis.

0.470g soybean lecithin (EPIKURON 200) was mixed with 0.185g "Tung-Sorbitol product" and 0.368g water. To this was added 0.198 g of potassium nitrate and mixed thoroughly. The torpedo nicotinic acetylcholine receptor formulation was prepared as described in previous examples. In this formulation, every 50 micrograms of receptor protein was contained in 50 microliters of lipid, mostly dioleoylphosphatidylcholine (DOPC). 25 mg of the formulation was added to the ultrastructured inverse bicontinuous cubic phase material-potassium carbonate mixture and the entire mixture was stirred gently but long enough to ensure good mixing. An upper layer solution was prepared by adding 0.128 g of PLURONIC F-68 and 0.015 g of cetylpyridinium bromide to 6.05 g of a saturated aqueous solution of potassium nitrate. The ultrastructure inverse bicontinuous cubic phase substance-potassium nitrate preparation was heated to 40°C to dissolve the potassium nitrate, and then immersed in 10°C water for 10 minutes. The supernatant solution was overlaid on a test tube containing the receptor-loaded ultrastructural inverse bicontinuous cubic phase material, which was sealed, shaken, and sonicated for 2 hours. A dispersion of potassium nitrate-coated receptor-containing microparticles was produced, mostly in the size range of 0.3 to 1 micron.

The microparticles were then immobilized in a polyacrylamide hydrogel. Acrylamide (0.365g), methylenebisacrylamide (0.049g, as a crosslinking agent), ammonium persulfate (0.072g 2% solution, as an initiator) and tetramethylenediamine (TMED, 0.011g , as a co-initiator) was added to the dispersion to allow acrylamide to polymerize and cross-link the hydrogel within a few hours. Observation of a thin slice of this hydrogel under a microscope reveals a high concentration of microparticles (except near the bottom of the hydrogel), exactly the same as the original dispersion.

The hydrogel was further broken into small pieces of about 30 microns in size. This is achieved by pressing the hydrogel through a metal sieve with a mesh size of 40 microns. At a size of 40 microns, the diffusion time of small molecules into the center of the block can be estimated to be about 1 second or less, which has no appreciable effect on subsequent receptor test reports.

Receptor binding assays were performed using the ultrastructural inverse bicontinuous cubic material particle-immobilized acetylcholine receptor system just described using ¹²⁵ I-labeled krait venom as ligand. (Standard binding assays have been described in publications by Dr. Mark McNamee's group). The results showed that the ultrastructured inverse bicontinuous cubic phase material microparticle-immobilized acetylcholine receptor system exhibited binding to Bungarovenom at about 70% of the level measured with standard receptor preparations, demonstrating that not only throughout the immobilized Protein binding was maintained during the procedure and remained after a period of time (greater than two months) between sample preparation and testing.

Examples 26-28 above actually demonstrate the use of the particles in biochemical assays, demonstrating a much improved stability over commonly used liposomes, which are inconvenient due to their inherent instability. Such tests are valuable in clinical diagnosis as well as in drug screening.

Example 29

As in previous Example 22, clathrate-coated particles were produced in this example. In this example, the ultrastructured inverse bicontinuous cubic species is internally polymerizable by the action of oxygen that passes through the coating (the coating still prevents the passage of water).

Krill-derived lecithin is obtained from Avanti Polar Lipids of Birmingham, Alabama in the form of Krillshrimp phosphatidylcholine. 0.220 g of this lecithin was mixed with 0.110 g of the "tung-sorbitol product", 0.220 g of water, 0.005 g of cobalt desiccant containing cobalt naphthenate (from Grumbacher, the material supplier), and 0.30 g of potassium thiocyanate. An inverse bicontinuous cubic phase material forming a green ultrastructure. An upper layer solution was prepared by adding 0.309 g of manganese chloride, 0.105 g of 4-picoline, 0.113 g of PLURONIC F-68 and 0.021 g of cetylpyridinium bromide to 5.10 g of water. The supernatant solution was overlaid on top of the ultrastructured inverse bicontinuous cubic phase material, and the tube was sealed, shaken, and sonicated, using ice water as the water for the sonication bath. The reaction turns the color to brown as the green ultrastructured inverse bicontinuous cubic phase material is dispersed into the microparticles. After 2 hours, essentially all of the ultrastructured inverse bicontinuous cubic phase material had dispersed into the particles, which were mostly submicron. The coating is a Werner compound which, according to literature, has channels that allow the uptake (or passage) of molecular oxygen. The high degree of unsaturation of krill lecithin (and the tung-sorbitol product) combined with the catalysis of the cobalt driers makes it possible for this microencapsulated ultrastructured inverse bicontinuous cubic phase material to polymerize upon exposure to atmospheric oxygen .

The clathrates in this example were discussed previously (Example 22).

Example 30

This example is an inverse hexagonal phase material with dispersed ultrastructure.

0.369 g of soybean lecithin (EPIKURON 200), 0.110 g of sorbitan trioleate and 0.370 g of glycerol were mixed to prepare an ultrastructured reverse hexagonal phase material. To this ultrastructured inverse hexagonal phase material was added 0.054 g of magnesium sulfate. Add 0.10 g of potassium carbonate, 0.10 g of PLURONIC F-68 and 0.02 g of cetylpyridinium bromide to 5 g of water to prepare an upper layer solution. Cover the upper layer solution on the reverse hexagonal phase substance of the ultramicrostructure, seal the test tube, shake, and sonicate for 1 hour, and obtain the reverse hexagonal phase substance of most ultrafine structure as the dispersion of particles coated by basic magnesium carbonate body.

The dimensionality of the inverse hexagonal mesopores (cylindrical) provides a unique release kinetic profile that can be used eg for controlled drug delivery.

Example 31

Contrary to most of the above examples, the dispersed ultrastructured inverse hexagonal phase material in this example is not in equilibrium with excess water, although it is insoluble in water.

Soy lecithin (0.412g), linseed oil (0.159g) and glycerol (0.458g) were thoroughly mixed to produce an ultrastructural reverse hexagonal phase material at room temperature. To this ultrastructured inverse hexagonal phase material was added 0.059 g of magnesium sulfate. Add 0.10 g of potassium carbonate, 0.10 g of PLURONIC F-68 and 0.02 g of cetylpyridinium bromide to 5 g of water to prepare an upper layer solution. Cover the upper layer solution on the reverse hexagonal phase material of the ultramicrostructure, seal the test tube, shake, and sonicate for 30 minutes, and obtain the reverse hexagonal phase material of most ultramicrostructures as the dispersion of particles coated by basic magnesium carbonate body.

The ability to disperse ultrastructural phases that are not in equilibrium with excess water expands the range of chemistry that can be used in the present invention. This versatility is especially important in demanding applications such as drug delivery, where many product criteria must be met simultaneously.

Example 32

In this example, a chemical reaction method is used to disperse the ultrastructured lamellar phase material.

An ultrastructured lamellar phase material was prepared by mixing 0.832 g soybean lecithin (EPIKURON 200) with 0.666 g water. To about 0.80 g of the ultrastructured lamellar phase material was added 0.057 g of magnesium sulfate. Add 0.10 g of potassium carbonate, 0.10 g of PLURONIC F-68 and 0.02 g of cetylpyridinium bromide to 5 g of water to prepare an upper layer solution. Cover the upper layer solution on the ultrastructured layered phase material, seal the test tube, shake, and sonicate for 5 minutes to obtain a majority of the ultrastructured layered phase material as a dispersion of particles coated with basic magnesium carbonate. body.

The particles in this example are structurally related to polymer-encapsulated liposomes, but are not subjected to the harsh chemical conditions used to produce polymer-encapsulated liposomes; can be produced in a single step and under mild conditions using a wide range of The crystalline coating-coated inner lamellar phase particles make the present invention valuable in controlled-release drug delivery.

Example 33

Preparation of free base

Buy Norquinine and Neutral Red in the protonated HCl form. In each case the salt was dissolved in water, to which was added aqueous sodium hydroxide in a 1:1 molar ratio. The mixture of the two aqueous solutions produced a precipitate which was washed with water (to remove NaCl and any unreacted NaOH), centrifuged and then dried above the melting point of the free base.

Preparation of Ultrastructured Inverse Bicontinuous Cubic Phase Dispersion

Start the dispersion with the following mixture:

0.417gm Glyceryl Monooleate (GMO)

0.191gm glycerin

0.044gm Ethylhydronorquinine (or, as an example, Neutral Red, both in free base form).

Instead of the commonly used monoglyceride-water ultrastructured inverse bicontinuous cubic species, the monoglyceride-glycerol ultrastructured inverse bicontinuous cubic species was used in these examples.

Dissolve PLURONIC F-68 in water to a concentration of 2% to prepare a supernatant solution.

After weighing the components into the test tube and mixing with a spatula, place the sealed (twist cap) test tube in an oven at 140°C for at least 20 minutes and check that the ethylhydronorquinine (or neutral red free base) has melted. The test tubes were then immersed in water, which in some cases was below room temperature (about 10° C.) and in others at room temperature; no difference was found in the dispersions in both cases.

After about 5 minutes of the sample in cold water, a very high viscosity was detected, indicative of an inverse bicontinuous cubic phase of the ultrastructure; in some cases the optical isotropy of the sample was observed by cross-polarization (crystalline coating domains vs. light wavelength much smaller, too small to affect the optical properties). Fill the tube with PLURONIC supernatant solution to about half full. The tubes were then shaken (by hand and with a mechanical mixer). The solution gradually becomes opaque as the inverse bicontinuous cubic phase material of the host ultrastructure disappears to become a dispersion.

SEM characterization

Scanning electron microscopy (SEM) preparations do not involve any fixation techniques. A drop of the dispersion was simply placed on a glass slide, the water evaporated and a thin (2nm) layer of carbon sprayed on to avoid charging interactions. In the sparging apparatus, carefully hold the sample under a vacuum of 5 x 10 ^-4 Torr for about 5 minutes before starting sparging. This is done to test the robustness of the particle coating. The SEM used was a Hitachi S-800 field emission SEM operated at 25kV.

Figure 3 shows a SEM micrograph of a dihydronorquinine dispersion, showing particle sizes in the range of about 0.5-2 microns (the lower half is 10 times the area separated in the upper half, so the upper magnification is 500 and the magnification below is 5000). It is noteworthy that many of the particles clearly exhibit polyhedral shapes.

Measurements of the particle size distribution of this sample (see below) indicated that the dispersion was dominated by particles of about 0.5-2 microns in diameter, which was in good agreement with the particles seen in the photomicrograph. The thickness of the norquinine coating in the 0.5 micron particles can be estimated to be about 10 nm, which is apparently sufficient to keep the liquid components inside the particles from evaporating in a 0.5 mTorr vacuum.

In this dispersion, the ultrastructured inverse bicontinuous cubic phase material was loaded with lithium sulphate as a marker before dispersion and indeed the EDX spectrum of the particles in this dispersion showed peaks of sulfur. The EDX used was unable to detect lithium and other peaks in the spectrum were attributed to the glass matrix.

Figure 4 shows a SEM micrograph of a neutral red dispersion. Essentially all particles are in the range of 0.3-1 micron.

Particle size distribution

The particle size distribution was measured with a Malvern 3600E laser diffraction particle size analyzer. For each dispersion to be examined, a few drops are added to the carrier fluid (water) to allow a large dilution of the concentration to avoid multiple scattering. Particle size is calculated as the diameter of a sphere of equal volume, which is a good measure considering the polyhedral shape of the particles. (see below). The instrument is capable of measuring particles down to at least 0.5 microns, and the data on the distribution includes contributions at least down to 0.5 microns.

The particle size distribution of the dispersion prepared with 13:1 GMO:Norquinine is shown in FIG. 5 . In general, as the ratio of ultrastructural inverse bicontinuous cubic species to crystallographic coating agent increases, the particle size also increases. The data for this dispersion show that 10% of the particles on a volume average have a particle size of less than 0.6 microns, which is expressed by the equation D(v,0.1)=0.6 microns. The narrowness of the distribution is expressed in two ways. First, D(v,0.9) and D(v,0.1) are both doubled by a (volume-weighted) average of D(v,0.5)=1.2 microns. Second, calculate "span" as 1.4, "span" gives the width of the distribution as:

span=[D(v,0.9)-D(v,0.1)]/D(v,0.5)

These results indicate a very low degree of agglomeration.

GMO:neutral red=10:1 dispersion distribution is narrower. With a span of 1.1, it is evident that the (differential) particle size distribution is rather steep, falling off rapidly beyond 2 microns.

Dispersions prepared with lower GMO:Norquinine ratios were measured to have smaller particle sizes with a distribution average of 0.8 microns and a span of 1.2. Thus, the particles can be controlled by the ratio of the ultrastructural inverse bicontinuous cubic phase species to the crystalline coating agent, the ratio decreases and the particle size decreases.

Small Angle X-ray Scattering (SAXS)

This is used to verify that the interior of the particles in the ethylhydronorquinine dispersion is an anti-bicontinuous cubic phase material with ultrastructure. The dispersion itself (not the concentrate of particles) was loaded into a 1.5 mm x-ray capillary and sent to the laboratory of Dr. Stephen Hui at Roswell Park Cancer Center Biophysics Department. The SAXS camera is equipped with a rotating positive electrode and measures at 100kV, 40mV power (4kW). Data were collected with a linear position sensitive detector electronically connected to a Nuceus multichannel analyzer. The MCA has a capacity of 8,192 channels, but adds only 2,048 resolution per channel count. A counting time of about 1 hour was used because the volume fraction of ultrastructured inverse bicontinuous cubic species in the dispersion (which was about 85% of the particle volume) was about 10%. Data were analyzed with the software package "PCA".

Figure 6 shows the measured SAXS intensity versus wave vector q. The wave vector q is related to the diffraction angle θ and wavelength λ of x-rays by the following formula:

q=4π(sinθ)/λ.

The d-spacing is calculated from the q-value of the Bragg reflection:

d=2π/q.

In Figure 6, the vertical lines give the exact calculated Bragg peak positions for a lattice with space group Pn3m and lattice parameter 7.47nm. This space group is well established for ultrastructural inverse cubic phases in monoolein-water systems, especially for those in equilibrium with excess water. (Indeed, in the ultrastructured anti-cubic phase in equilibrium with excess water, the space group Pn3m occurs almost exclusively). The lattice parameter of the monoolein-water ultrastructured inverse cubic phase with space group Pn3m is also close to 8 nm; a more precise comparison is not possible because glycerol is used instead of water in this case. In any case, the lattice type and size deduced from this SAXS scan agree exactly with literature data for the inverse cubic phase of the monoglyceride ultrastructure.

In space group Pn3m, the values of Miller index (hkl) and h ² +k ² +l ² for the allowed peak positions are: (110), 2; (111), 3; (200), 4; (211) , 6; (220), 8; (221), 9; (222), 12; and higher. Looking at these data and the predicted peak positions, it is clear that the peaks at positions (110) and (222) are strongly supported by the data. The (111) peak appears to be a shoulder of the (110) peak on the right side of the scan and a small but discernible peak on the left. The (200) peak is supported at least on the right side of the scan; this peak is always much less intense than the (110) and (111) peaks when measured in the monoglyceride Pn3m phase, generally in the Pn3m phase, which has been found to be Consistent with theoretical amplitude calculations [Strom, P. and Anderson, DM (1992) Langmuir, 8:691]. The (211) peak is supported by the data on the left side of the scan and (221) by the data on the right side. The lack of or low peak intensity between (211) and (222) is a consequence of the low (10%) concentration of the ultrastructured inverse bicontinuous cubic phase in the dispersion, since the diffracted x-ray intensity is proportional to the square of the volume concentration . Despite this, the decisive peaks at (110) and (222) and the deduced lattice and lattice parameters are completely consistent with the relevant systems in the literature. It provides a conclusion that the SAXS data proves the anti-bicontinuous cubic phase ordering of the internal ultrastructure of the particles. Strong support.

These particles can be used, for example, for the controlled release of bactericides in mouthwashes, where the solubility of both coatings at slightly lower pH (about 5) is well within the range of preferential delivery to bacterial active sites.

Example 34

High-pressure liquid chromatography (HPLC) was used to characterize the integrity of two dispersions under shear and pressure, one selected as a hard coating - copper ferrocyanide, and the other as a soft, breakable coating, which Primarily as a control to determine how much harder coatings release under pressure. In other words, if the concentration of marker in the two dispersions is approximately the same, and the release of marker from the hard system is a fraction of the release of marker from the soft system, i.e. a percentage x% (where x is significantly less than 100), it can be concluded that Only x% of the particles in the system ruptured under this pressure, the remaining (100-x)% remained intact during the HPLC. (Indeed, this percentage 100-x is a lower limit: if it is found that some soft particles in the control actually remain intact, although this is very unlikely, the actual percentage of intact hard particles is calculated to be higher. In any case, the calculation is assumed to be Based on the worst case scenario, all control particles were assumed to be broken.)

Preparation of dispersion

Example 34A

0.499g soybean lecithin, 0.163g oleyl alcohol, 0.900g glycerol and 0.124g capsaicin were mixed to prepare an ultrastructured inverse bicontinuous cubic phase material. To 0.842 g of the ultrastructured inverse bicontinuous cubic phase material from this system was added 0.043 g of sodium cholate. Add 1 drop of 1M HCl to 3.00 g pH 5 phosphate buffer to prepare the upper layer solution. The supernatant solution was overlaid on the liquid crystal substance, the test tube was sealed and sonicated to obtain a milky white particle dispersion.

Example 34B

0.329g soybean lecithin, 0.108g oleyl alcohol, 0.611g glycerol and 0.105g capsaicin were mixed to prepare an ultrastructured inverse bicontinuous cubic phase material. 0.046 g of copper sulfate was added thereto. Add 0.563g of 10% potassium ferrocyanide solution to 2.54g of water to prepare the upper layer solution. The supernatant solution was overlaid on the liquid crystal, the test tube was sealed and sonicated to obtain a milky white dispersion of microparticles coated with copper ferrocyanide.

The concentration of the marker, capsaicin, was comparable in both samples. The final concentration in the copper ferrocyanide dispersion was 2.44%, Example 34B was 3.19%, a difference of 30%, which is explained in the calculations below.

Pure capsaicin was then tested in HPLC and the elution time was measured to be 22 minutes (data not shown). Under the same conditions, the two dispersions prepared as above were tested. The data for the Example 34B particles are shown in FIG. 7 and the data for the copper ferrocyanide particles are shown in FIG. 8 . Tables 1 and 2 give the integrated peaks corresponding to Figures 7 and 8, respectively, which are output by an HPLC computer with a sampling rate of 5 Hz.

Clearly, there is a strong peak (peak 13 marked by computer) at an elution time of 22 minutes in Figure 7, and Table 1 gives an integrated intensity of 3,939,401 for this peak. It can be seen in Figure 8 that the peak at 22 minutes is much smaller (marked by the computer as 10), and Table 2 gives an intensity of 304,929.

If these integral peaks are normalized by the concentration of capsaicin in the two samples, that is, embodiment 34B is 3,939,401/0.0319, and copper ferrocyanide is 304,929/0.0244, then the normalization of copper ferrocyanide and embodiment 34B The ratio of peak intensities was 0.101, that is, at most 10.1% of the copper ferrocyanide particles released the capsaicin label under HPLC conditions.

These particles have an inorganic coating of low water solubility, making them potentially useful in applications requiring release of the particle coating by strong shear while preventing release by simple dilution with water. Examples of such applications are encapsulation of rodent deterrents such as capsaicin or rodent toxins, impregnation of particles into electrical wires, corrugated boxes and other products requiring protection from rodent gnawing, which will result in active To prevent the release of substances or toxins. Low water solubility prevents premature release of barriers due to wet conditions.

Table 1 : Integrated peak intensities, corresponding to Figure 7, for HPLC analysis of capsaicin-containing particles of Example 34B. Peak #13 is the main capsaicin peak.

Peak area

1 2914

2 8096

3 2848

4 29466

5 11304

6 2254

7 12871

8 4955

9 124833

10 113828

11 19334

12 7302

13 3939401

14 39153

15 255278

16 755868

17 52623

18 19395

19 4899

20 10519

21 5102

22 1481

23 344230

24 9971

25 194442

26 89831

27 80603

28 105163

29 186224

30 194020

31 36805

32 2115

33 23296

34 4327

35 5166

36 90236

37 62606

38 44523

39 110347

40 4391

41 1275597

42 1353000

43 238187

Table 2: Integrated peak intensities, corresponding to Figure 8, for HPLC analysis of copper ferrocyanide-coated capsaicin-containing particles. Peak #10 is the main capsaicin peak.

Peak area

1 1681172

2 3011240

3 106006

4 2760

5 59059

6 38727

7 163539

8 44134

9 6757

10 304929

11 10466

12 141800

13 332742

14 14442

15 6996

16 15008

17 11940

19 91446

20 250214

21 251902

22 203000

23 44658

24 110901

25 24296

26 19633

27 25527

28 15593

29 75442

30 40245

31 421437

Example 35

0.77 g of soybean lecithin (EPIKURON 200 from Lucas-Meyer), 0.285 g of oleyl alcohol and 0.84 g of glycerin were mixed to prepare an ultrastructured cubic phase liquid crystal, to which 0.11 g of gold chloride was added. No heat was used in the equilibration of the mixture, only mechanical stirring with a spatula. 0.595 g of this mixture was removed and spread along the lower half of the inner surface of the test tube. Prepare an upper layer solution by dissolving 0.14 g of ferrous chloride and 0.04 g of PLURONIC F-68 in 1.74 g of distilled water. The overlying solution was overlaid, and the tube containing the cubic phase was then sonicated to obtain a gold-coated microparticle dispersion. Sonication of a control sample (in which the top solution contained F-68 but no ferrous chloride) alongside the first sample did not produce a particle dispersion. The reaction between ferrous chloride and gold oxide leads to the precipitation of elemental gold which is non-lamellar crystalline, producing in the case of the first sample gold-coated particles with a cubic phase interior.

0.62 g of glycerol was then mixed with 0.205 g of water to prepare a glycerol-water mixture having a density of about 1.2 g/cc, to which was added about 0.1 g of the dispersion, and the new dispersion was centrifuged. Most of the particles were centrifuged to the bottom of the tube after 3 hours of centrifugation, demonstrating that the density of these particles was significantly higher than 1.2; this was due to the presence of the gold coating, as the density of the cubic phase was lower than 1.2 - indeed, it was not disturbed during the sonication. A fraction of the dispersed cubic phase was centrifuged from the original dispersion as a less dense group, indicating that the liquid was less dense than the original dispersion.

Because gold is known to exhibit chemical inertness and good mechanical properties in the form of very thin films, and since it is also FDA-approved for many regulatory pathways, gold-coated particles can be used in demanding chemical and Physically stable coated product. Furthermore, such particles are effective in the treatment of arthritis, providing a significantly increased gold surface area compared to other colloidal forms.

Example 36

Dissolve 0.045g paclitaxel, 0.57g eugenol, 0.615g soybean lecithin (EPIKURON 200), 0.33g glycerol and 0.06g copper nitrate with 0.61g methanol to prepare the ultrastructural liquid phase containing the antineoplastic drug paclitaxel, and then in an evaporating dish The methanol was evaporated, stirring during evaporation. Prepare a glycerol-rich upper layer solution by dissolving 0.09g potassium iodide, 0.05g PLURONIC F-68, 0.44g water and 1.96g glycerol. The overlying solution was overlaid and the system was sonicated to produce a dispersion of an ultrastructured liquid phase containing paclitaxel encapsulated within microparticles by crystalline iodine. Since these components were chosen for their generally accepted safety in pharmaceuticals as blunt excipients (except for paclitaxel itself), this formulation or variants thereof are of value in the delivery of paclitaxel for the treatment of cancer. The loading of paclitaxel inside the particles is quite high, i.e. about 3% by weight, in this case it is so high that some paclitaxel inside each particle is metastable due to the dissolution of paclitaxel in the cubic phase at this high loading. Precipitation may occur. However, studies have shown that precipitation under such loads is very slow, taking hours or even days, so that essentially all paclitaxel remains in solution during the production of the granules; paclitaxel is then confined within the coated granules preventing the formation of large crystals (greater than 1 micron). If the concentration of paclitaxel in this system is reduced to 0.7% or less of the interior, the dissolution of paclitaxel becomes a truly stable solution (thermodynamic equilibrium), thereby completely preventing precipitation, and the present invention coated with non-lamellar crystalline iodine Microparticles can be produced as described in this example. Thus, this system offers several options for the delivery of paclitaxel for the treatment of cancer.

Example 37

Cubic phase liquid crystals containing paclitaxel were prepared by mixing 0.345 g soybean lecithin (EPIKURON 200), 0.357 g anisole, 0.26 g water and 0.02 g paclitaxel (from LKT Laboratories); after vigorous stirring, the test tube of this mixture was immersed in boiling water for 1 minute, It is then cooled to room temperature to accelerate equilibration. To provide the coating material, 0.07 g of propyl gallate was stirred in and the tube was heated in boiling water. It has previously been examined that propyl gallate is not properly soluble in this cubic phase at room temperature, but the solubility increases significantly at 100°C. The upper layer solution is made up of 2.25g 2% PLURONICF-68 solution. The cubic phase-propyl gallate mixture was heated to 100°C, cooled to about 80°C, stirred with a spatula at this high temperature, and then heated to 100°C. The mixture was cooled for about 30 seconds, then the supernatant solution was overlaid on the mixture and the tube was placed in the sonication bath for 1 hour. A dispersion of microparticles containing paclitaxel inside and coated with propyl gallate was obtained. The dispersion has a high concentration of very fine particles (estimated particle size less than 0.4 microns), which are observable by their Brownian motion in a light microscope at 100Ox. The total particle size distribution is quite broad, with some particles reaching 1-2 microns. Only very small amounts of precipitated paclitaxel (needles) were observed, so almost all paclitaxel was inside the microparticles. The concentration of paclitaxel in this example was high enough to make the solution metastable (as discussed in the previous examples). Since the concentration of the antineoplastic drug paclitaxel inside these granules is about 2%, the components of the formulation are blunt excipients listed by the FDA for oral delivery (they are almost injectable as well), and the formulation serves as Drug delivery formulations would be very valuable for the treatment of cancer.

Example 38

1.655 g of the amphiphilic polyethylene oxide-polypropylene oxide block copolymer PLURONIC F-68 (also known as POLOXAMER 188) was mixed with 0.705 g of eugenol and 2.06 g of water. After centrifugation, two phases are obtained, the lower phase is an ultrastructured liquid phase, and the upper phase is an ultrastructured cubic phase. 0.68 g of the liquid crystal phase was taken out, and 0.05 g of sodium iodide was added thereto. One drop of eugenol was added to 2.48 g of the lower phase to ensure low viscosity, and this ultrastructured liquid phase (to which 0.14 g of silver nitrate had been added) was used as the "top solution" in dispersing the liquid crystal phase. In this way, the liquid phase was overlaid on top of the iodide-containing liquid crystal phase, and the mixture was sonicated for 1.5 hours. The result is a dispersion of silver iodide-coated particles in the external medium of the ultrastructured liquid phase.

This example illustrates the use of an ultrastructural liquid crystalline phase based on block copolymers as the internal matrix of the particles of the invention. In this case, water acts as the preferred solvent for the polyethylene oxide segments of the block copolymer and eugenol acts as the preferred solvent for the polypropylene oxide segments of the block copolymer (it is not soluble in water).

This example also illustrates using the general method described above, ie using the ultrastructural phase as the mixture used as the "top solution", to provide Part B which reacts with Part A in the inner phase to cause precipitation of the crystalline coating material. In this example, B is silver nitrate, which precipitates silver iodide when in contact with the inner matrix A (cubic phase) containing sodium iodide. As previously stated, it is generally desirable to choose this upper solution so that it is in equilibrium with the inner matrix, or in this case, very close to equilibrium (the only departure from true equilibrium is the addition of a drop of eugenol, about 0.01 g or less, to the upper solution. at 0.5%). In such methods, it is generally useful to select the inner matrix such that it is a viscous mass, much more viscous than the less viscous supernatant solution.

It will be apparent that many modifications and variations can be made in the present invention without departing from the spirit and scope of the invention. It is to be understood that the invention is not to be limited to the exact interpretations and arrangements described herein, but such modifications are within the scope of the appended claims. Specific embodiments are illustrated by way of example only, and the invention is limited only by the claims.

Claims (57)

1. A coated particle comprising a. an inner core containing a matrix consisting essentially of the following components: i. At least one ultrastructural liquid phase, ii. at least one ultrastructured liquid crystal phase, or iii. A combination of the following components (1) At least one ultrastructural liquid phase, (2) at least one ultrastructured liquid crystal phase, and b. External coatings containing non-lamellar crystalline material. 2. The coated particle of claim 1, wherein said ultrastructural liquid phase material comprises a. Ultrastructure L1 phase material, b. Ultrastructure L2 phase material, c. Ultrastructure microemulsion or d. Ultrastructure L3 phase material. 3. The coated particle of claim 1, wherein said ultrastructured liquid crystal phase material comprises a. Ultrastructure normal or anti-cubic phase substances, b. Ultrastructure positive or negative hexagonal phase substances, c. Ultrastructure normal or anti-mesophase substances or d. Ultrastructure layered phase substances. 4. The coated particle of claim 1, wherein said ultrastructural liquid phase material comprises a. Polar solvents, b. Surfactants or lipids. 5. The coated particle of claim 1, wherein said ultrastructural liquid phase material comprises a. Polar solvents, b. Surfactants or lipids, and c. Amphiphiles or hydrophobes. 6. The coated particle of claim 1, wherein said ultrastructural liquid phase material comprises a. Block copolymers. 7. The coated particle of claim 1, wherein said ultrastructural liquid phase material comprises a. block copolymers, and b. Solvent. 8. The coated particle of claim 1, wherein said ultrastructured liquid crystal phase material comprises a. Polar solvents, and b. Surfactants. 9. The coated particle of claim 1, wherein said ultrastructured liquid crystal phase material comprises a. Polar solvents, b. Surfactants, and c. Amphiphiles or hydrophobes. 10. The coated particle of claim 1, wherein said ultrastructured liquid crystal phase material comprises a. Block copolymers. 11. The coated particle of claim 1, wherein said ultrastructured liquid crystal phase material comprises a. block copolymers, and b. Solvent. 12. The coated particle of claim 1, wherein said inner core comprises an active agent disposed within said matrix. 13. The coated particle of claim 10, wherein the active agent comprises paclitaxel. 14. The coated particle of claim 10, wherein the active agent comprises capsaicin. 15. The coated particle of claim 10, wherein the active agent comprises a photodynamic therapy agent. 16. The coated particle of claim 10, wherein the active agent comprises a receptor protein. 17. The coated particle of claim 1, wherein said inner core comprises an inverse cubic phase material. 18. The coated particle of claim 17, wherein said inner core comprises an active agent distributed within said matrix. 19. The coated particle of claim 18, wherein the active agent comprises paclitaxel. 20. The coated particle of claim 18, wherein the active agent comprises capsaicin. 21. The coated particle of claim 18, wherein the active agent comprises a photodynamic therapy agent. 22. The coated particle of claim 18, wherein the active agent comprises a nucleic acid. 23. The coated particle of claim 18, wherein the active agent comprises a glycolipid. 24. The coated particle of claim 18, wherein the active agent comprises an amino acid. 25. The coated particle of claim 18, wherein the active agent comprises a polypeptide. 26. The coated particle of claim 18, wherein the active agent comprises a protein. 27. The coated particle of claim 18, wherein the active agent comprises an antineoplastic therapeutic agent. 28. The coated particle of claim 18, wherein the active agent comprises an antihypertensive therapeutic agent. 29. The coated particle of claim 18, wherein the active agent comprises a rodent deterrent. 30. The coated particle of claim 18, wherein the active agent comprises a pheromone. 31. The coated particle of claim 18, wherein the active agent comprises a receptor protein. 32. The coated particle of claim 1, wherein said matrix comprises a substance having the physicochemical properties of a biofilm. 33. The coated particle of claim 32, wherein said biofilm material comprises a biologically active polypeptide material. 34. The coated particle of claim 32, wherein said matrix comprises a polypeptide or protein immobilized in said biofilm. 35. The coated particle of claim 1, wherein said outer coating comprises a non-layered crystalline material having a solubility in water of less than about 10 grams per liter of water. 36. The coated particle of claim 1, wherein said outer coating comprises clathrate material. 37. The coated particle of claim 1, wherein said outer coating comprises a clathrate. 38. The coated particle of claim 1, wherein said outer coating comprises a zeolite material. 39. A method of making coated particles comprising a. an inner core containing a matrix consisting essentially of the following components: i. At least one ultrastructural liquid phase, ii. at least one ultrastructured liquid crystal phase, or iii. A combination of the following components (1) At least one ultrastructural liquid phase, (2) at least one ultrastructured liquid crystal phase, and b. External coatings containing non-lamellar crystalline substances The method includes providing a volume of said matrix comprising at least one chemical species having a moiety capable of reacting with a second moiety to form a non-lamellar crystalline material, and contacting said amount of substrate with a fluid containing at least one chemical substance having said second moiety, such that said first moiety reacts with said second moiety while imparting to said amount of The matrix applies energy to subdivide it into particles. 40. A method of making coated particles comprising a. an inner core containing a matrix consisting essentially of the following components: i. At least one ultrastructural liquid phase, ii. at least one ultrastructured liquid crystal phase, or iii. A combination of the following components (1) At least one ultrastructural liquid phase, (2) at least one ultrastructured liquid crystal phase, and b. External coatings containing non-lamellar crystalline substances The method includes providing an amount of said matrix comprising said non-lamellar crystalline material dissolved therein, and The non-lamellar crystalline material is rendered insoluble in the matrix while energy is applied to the amount of matrix to subdivide it into particles. 41. A method of making coated particles comprising a. an inner core containing a matrix consisting essentially of the following components: i. At least one ultrastructural liquid phase, ii. at least one ultrastructured liquid crystal phase, or iii. A combination of the following components (1) At least one ultrastructural liquid phase, (2) at least one ultrastructured liquid crystal phase, and b. External coatings containing non-lamellar crystalline substances, The method includes providing an amount of said matrix comprising a non-lamellar crystalline material dissolved therein and comprising at least one chemical species having a moiety capable of reacting with a second moiety to form said non-lamellar crystalline material, and contacting said amount of substrate with a fluid containing at least one chemical species having said second moiety such that said first moiety reacts with said second moiety while causing said non-lamellar crystallization The substance becomes insoluble in the matrix, and energy is applied to the volume of matrix to subdivide it into particles. 42. A method of making coated particles comprising a. an inner core containing a matrix consisting essentially of the following components: i. At least one ultrastructural liquid phase, ii. at least one ultrastructured liquid crystal phase, or iii. A combination of the following components (1) At least one ultrastructural liquid phase, (2) at least one ultrastructured liquid crystal phase, and b. an outer coating comprising a first non-layered crystalline material and a second non-layered crystalline material, The method includes providing an amount of said matrix comprising dissolved therein a first non-layered crystalline material and comprising at least one chemical species having a property capable of reacting with a second moiety to form a second non-layered crystalline material part, and contacting said amount of substrate with a fluid containing at least one chemical substance having said second moiety such that said first moiety reacts with said second moiety while causing said first non-layer The crystalline material becomes insoluble in the matrix and energy is applied to the volume of matrix to subdivide it into particles. 43. A method of using coated particles comprising a. an inner core containing a matrix consisting essentially of the following components: i. At least one ultrastructural liquid phase, ii. at least one ultrastructured liquid crystal phase, or iii. A combination of the following components (1) At least one ultrastructural liquid phase, (2) at least one ultrastructured liquid crystal phase, and b. External coatings containing non-lamellar crystalline substances, The method includes Dispensing the particles into a fluid medium containing an adsorbable substance adsorbs the adsorbable substance onto the outer coating. 44. A method of using coated particles comprising a. an inner core containing a matrix consisting essentially of the following components: i. At least one ultrastructural liquid phase, ii. at least one ultrastructured liquid crystal phase, or iii. A combination of the following components (1) At least one ultrastructural liquid phase, (2) at least one ultrastructured liquid crystal phase, and b. External coatings containing non-lamellar crystalline substances, The method includes The particles are dispensed into a fluid medium containing an absorbable substance which is absorbed in the inner core. 45. The method of claim 44, wherein said absorption is initiated by dissolution of said outer coating by said fluid medium. 46. The method of claim 44, wherein said absorption is initiated by splitting of said outer coating. 47. The method of claim 44, wherein said absorption occurs through pores in said outer coating. 48. A method of using coated particles comprising a. an inner core containing a matrix consisting essentially of the following components: i. At least one ultrastructural liquid phase, ii. at least one ultrastructured liquid crystal phase, or iii. A combination of the following components (1) At least one ultrastructural liquid phase, (2) at least one ultrastructured liquid crystal phase, and b. External coatings containing non-lamellar crystalline substances, The method includes The particles are dispensed into a fluid medium containing an absorbable substance, and the absorbable substance is absorbed in the outer coating. 49. A method of using coated particles comprising a. an inner core containing a matrix consisting essentially of the following components: i. At least one ultrastructural liquid phase, ii. at least one ultrastructured liquid crystal phase, or iii. A combination of the following components (1) At least one ultrastructural liquid phase, (2) at least one ultrastructured liquid crystal phase, and b. External coatings containing non-lamellar crystalline substances, The method includes The particles are dispensed into a fluid medium containing an absorbable substance which is absorbed in the inner core and outer coating. 50. A method of using coated particles comprising a. an inner core containing a matrix consisting essentially of the following components: i. At least one ultrastructural liquid phase, ii. at least one ultrastructured liquid crystal phase, or iii. A combination of the following components (1) At least one ultrastructural liquid phase, (2) At least one ultrastructure liquid crystal phase, the matrix contains the active agent distributed therein, and b. External coatings containing non-lamellar crystalline substances, The method includes The particles are dispensed into a fluid medium, and the active agent is released into the fluid medium. 51. The method of claim 50, wherein said releasing is initiated by said fluid medium dissolving said outer coating. 52. The method of claim 50, wherein said release is initiated by disintegration of said outer coating. 53. The method of claim 50, wherein said release occurs through pores in said outer coating. 54. A method of using coated particles comprising a. an inner core containing a matrix consisting essentially of the following components: i. At least one ultrastructural liquid phase, ii. at least one ultrastructured liquid crystal phase, or iii. A combination of the following components (1) At least one ultrastructural liquid phase, (2) At least one ultrastructure liquid crystal phase, the matrix contains the active agent distributed therein, and b. External coatings containing non-lamellar crystalline substances, The method includes The active agent is released. 55. The method of claim 54, wherein said release is initiated by dissolution of said outer coating by said fluid medium. 56. The method of claim 54, wherein said release is initiated by cleavage of said outer coating. 57. The method of claim 54, wherein said release occurs through pores in said outer coating.

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